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ANTI-AGING STRATEGIES FOR WOMEN 50 YEARS AND OLDER: COMBATING MENOPAUSE, OSTEOPOROSIS, AND HEART DISEASE


- Dr. James Meschino, DC, MS, ROHP

Female Hormones and Aging

In today’s world both men a women are living longer than ever before as a result of better sanitation and hygiene practices, modern medical care, technologies to fight infections diseases, and greater availability of food. For the first time in history, modern women now live one-third of their lives in the postmenopausal years, and knowing how to remain feeling good, looking good and remaining healthy and productive during these years demands that women 50 years and over begin to include additional natural interventions to their wellness program during this stage of life. It can be a challenge for menopausal women to combat the age-related changes that occur in this stage of life, but in this section I will explain the additional supplements you need to take in order to remain looking and feeling youthful, safely reduce menopausal symptoms, and reduce your risk of osteoporosis, heart attacks, breast cancer and other health problems prevalent among menopausal women. The challenge to slow the aging process in women over 50 years and older stems from the dramatic drop off in the synthesis of estrogen, progesterone and testosterone that occurs when a woman enters the menopausal stage of life, which greatly accelerates the rate at which a woman’s body will age, and puts her at increased risk for certain life threatening degenerative disease, such as osteoporosis and heart disease. The truth is that adherence to a healthy diet and exercise program and maintaining a positive mental attitude, although the first vital steps to slow aging, and to reduce risk of degenerative diseases, these alone are not sufficient to combat the profound effects on aging and disease risk induced by the significant decline in production of estrogen, progesterone and testosterone that accompany the menopausal years of a woman’s life. Specific natural supplements should be added to the program when menopause appears. However, before I tell what additional supplement to include I want you to understand the changes that go on in your body during menopause so you can more fully appreciate the recommendations I have seen work for many women over the years.

The Cause and Effects of Estrogen and Progesterone Decline

Here’s how the menopausal story begins. As a woman approaches 50 years old her ovaries become less responsive to the hormones known as follicle stimulating hormone (FSH) and luteinizing hormone (LH), which are normally released by the pituitary gland in the brain to initiate the start of the next menstrual cycle. Throughout a woman’s fertile years, at the end of each menstrual cycle the hypothalamus gland in the brain senses that blood levels of estrogen and progesterone have dropped off significantly. The hypothalamus then responds by releasing hormones that stimulate the pituitary gland to secrete FSH and LH. In turn, the release of FSH and LH into the bloodstream stimulates some of the immature egg cells in the ovaries to begin the maturation process that leads to one of the eggs outpacing the rest and bursting out of the ovaries (ovulation) around day fourteen, to enter the fallopian tube. As the egg cell undergoes maturation in the ovaries and after the ovulation process, it secretes estrogen. Eventually the egg cell in the fallopian tube begins to shrivel up and die after a number of days if it does not become fertilized by a sperm cell. When this occurs, estrogen levels in the bloodstream drop off, which is a signal to the hypothalamus to begin another menstrual cycle by releasing hormones that stimulate the release, once again, of FSH and LH from the pituitary gland. The majority of estrogen in woman’s body is made by these developing and mature egg cells. In addition, estrogen is also made by the adrenal glands and fat tissue and that is why there is still some estrogen secretion by a woman’s body after menopause when her menstrual cycles no longer occur. However, the amount of estrogen secreted by the adrenal glands and fat tissue is minimal compared to the amount of estrogen secreted by developing and mature egg cells during a normal menstrual cycle. For instance, during a woman’s fertile years her daily estrogen secretion is 250-300 micrograms per day. After menopause, estrogen production (now only from adrenal glands and fat tissue) drops to only 20 micrograms per day (a 90% decline). Thus, the estrogen secreted by egg cells during each menstrual cycle is the primary source of estrogen in a woman’s body.

As stated above, when a woman enters menopause, her ovaries become less responsive to the influence of FSH and LH. More specifically, this means that even though there are still about 10,000 immature egg cells still remaining in the ovaries as a woman enters the menopausal years, these egg cells do not undergo maturation upon stimulation from FSH and LH, hence ovulation does not occur, and no or little estrogen gets secreted. This accounts for the dramatic reduction in estrogen secretion that accompanies menopause. (At birth women have about one million immature egg cells in their ovaries, and she normally releases 300-400 eggs from her ovaries upon ovulation during her fertile years; at a usual rate of one per month). The resulting drop off in estrogen that occurs in menopause has far reaching effects on the acceleration of aging and the development of degenerative conditions. Some of the menopausal signs and symptoms that are attributable, in part, to the reduction in estrogen include, reduced energy, forgetfulness, skin dryness, a drying up of mucus membranes throughout the body including the vagina, atrophy or thinning of the skin and vaginal tissue, decreased libido, changes in hair texture with increasing sparseness and graying, emotional mood swings and anxiety. As if this isn’t bad enough, the decline in estrogen also encourages the loss of calcium from bone, setting the stage for osteoporosis, and decreases a woman’s ability to clear cholesterol from the bloodstream, which increases her risk of heart attack and stroke.

Now what about progesterone? Where does it come from and what effects result from its decline during menopause? Well, the part of the maturing egg follicle that gets left behind in the ovary after ovulation occurs, known as the corpus luteum, is the primary source of progesterone secretion in a woman’s body. The corpus luteum also secretes some estrogen, but the secretion of progesterone is its primary function. Thus, when egg cells become unresponsive to the effects of FSH and LH, and stop maturing, there is a drop off in both estrogen and progesterone. In regards to progesterone, when a woman enters the menopausal years her blood levels of progesterone fall from 1.6 nanograms per milliliter to 0.5 nanograms per milliliters. This dramatic drop in progesterone secretion by the ovaries further promotes the development of osteoporosis, and is associated with decreased libido, skin thinning and atrophy.

In the grand scheme of things, the decline in estrogen and progesterone during menopause is known to play a large part in the acceleration of aging that occurs in women 50 plus years of age, and accounts for the increased risk osteoporosis and heart disease that is so prevalent in this population. But don’t be discouraged as there are natural, effective ways to conquer these problems and counter the aging effects of menopause if you so desire. Until recently, the medical profession encouraged the use of hormone replacement therapy to combat menopausal symptoms, as well as to reduce risk of osteoporosis in postmenopausal women. Although effective for these problems, hormone replacement therapy has been shown to increase risk of breast cancer, heart attack and stroke, and thus I strongly suggest that you use the natural and safer approaches to the management of menopause that I will outline in this section. But first lets examine the dangers of hormone replacement therapy that have come to light recently in order to better appreciate the more natural approach I will outline shortly.

The Dangers of Hormone Replacement Therapy

In recent years, many women across North America have demonstrated a reluctance to rely upon hormone replacement therapy (HRT) as a means to reduce menopausal symptoms, due primarily to concerns about the potential risk of breast cancer. In fact, only about 20% of women who are given a prescription for HRT actually follow through and take it faithfully. A growing number of postmenopausal women have been seeking out the use of herbal remedies as an alternative to HRT, as reflected by the rapid growth in herbal supplement sales during the past decade. Interest in natural therapies to control menopausal symptoms is expected to escalate due to two recent alarming reports, which confirm previous suggestions that hormone replacement therapy increases the risk of breast cancer and that unopposed estrogen (usually given to women who have undergone a hysterectomy) substantially increases the risk of ovarian cancer. On July 9, 2002, researchers announced that they were stopping the American Women’s Health Initiative (WHI) trial of 16,000 women taking hormone replacement therapy (HRT), as results showed that after 5.2 years there was a 26% increased risk of breast cancer in the women using hormone replacement than in women receiving the placebo. Women taking HRT also showed a 41% increased risk of stroke and a 29% increased risk of heart attack (myocardial infarction), compared to women receiving the placebo. Prior to this, many doctors promoted HRT as a means to reduce the risk of heart disease in postmenopausal women, but the findings of the WHI trial provide unequivocal evidence that, in fact, HRT greatly increases the risk of both heart attack and stroke in this population. More bad news regarding estrogen replacement therapy appeared in the July 17th, 2002, issue of the Journal of the American Medical Association. In a follow-up study of 44,241 former participants in the Breast Cancer Detection Demonstration Project, researchers discovered that the use of estrogen replacement therapy (without concurrent use of progesterone) increased risk of ovarian cancer, with a relative risk of 1.8 in women who used estrogen replacement therapy for 10-19 years and a 3.2 relative risk in women using estrogen replacement therapy for 20 or more years.
Previous data from the Nurses’ Health Study demonstrated that for each year a woman remained on HRT, her risk of developing breast cancer increased by 2.3%. Thus, a postmenopausal woman taking HRT for 10 years had a 23% increased risk of developing breast cancer, compared to women who were non-users of HRT. After 20 years of HRT use, a woman’s risk of developing breast cancer would be 46% greater than a women who never used HRT during the menopausal years, according to evidence provided by the Nurses’ Health Study. As the results of these studies get reported by the popular media, a growing number of women are giving up their HRT medications and searching for credible alternative means to optimize their feeling of well being, reduce hot flashes and other menopausal symptoms, maintain an active sex life and a healthy appearance, and reduce their risk of osteoporosis, heart disease and other degenerative conditions.

Don’t have time to read the whole book right now?

No worries. Let me send you a copy so you can read it when it’s convenient for you. Just let me know where to send it.

SIGNAL TRANSDUCTION, KEY RECEPTORS AND APOPTOSIS MECHANISMS IN CANCER

Dr. James Meschino, 

DC, MS, ROHP

The Need for a Safe Alternative to HRT

As I stated earlier, in today’s world, women live one-third of their lives in the postmenopausal years. Helping them maximize their quality of life, and lifespan, should be the intent of any nutrition, supplementation, or lifestyle recommendations, targeted to this group of women. In addition to controlling hot flashes and other menopausal symptoms, there are three major health concerns that must also be factored in to the nutrition, exercise and supplementation plan for women 50 years and older, as it is well established that postmenopausal women are at increased risk for breast cancer, osteoporosis, and heart disease.


• Heart disease is the number one killer of postmenopausal women
• Osteoporosis affects one in four women by age 50
• Breast cancer incidence rates have increased by 40% in the last 50 years, with one in every 403 women afflicted between ages 50-59, one in 266 women afflicted between ages 60-69, and one in 220 women afflicted at age 70 and over. Presently one in nine women in North America is expected to develop breast cancer during her lifetime, and one in 27 will die from this disease. It is the most frequently diagnosed cancer in women in this part of the world, accounting for 32% of all cancers in women.
Heart Disease
After menopause, women become less able to clear cholesterol from their blood stream. During the pre-menopausal stage of life, high circulating estrogen levels increase the production of LDL-cholesterol receptors, which enable cells to extract LDL-cholesterol (low density lipoprotein-cholesterol, which is known to increase risk of heart attack and stroke) from the blood stream and use it for various purposes. In menopause, there is a 90% drop off in circulating estrogen levels, which appears to reduce the ability of cells to produce LDL-cholesterol receptors. As a result there is a strong tendency for cholesterol to accumulate in the blood stream, stick to the walls of the arteries and cause narrowing of coronary blood vessels; leading to heart attack. As a high saturated fat diet is the main culprit in raising LDL-cholesterol levels, postmenopausal women should adjust their diet to lower their saturated fat intake (results from the Framingham Heart Study suggest individuals should ingest no more than 10 – 28 gms per day of saturated fat, based upon the presence of other risk factors such as family history, diabetes, smoking, high blood pressure etc), in order to keep their blood cholesterol levels below 200 mg per decilitre (5.2 milimoles per litre). This implies that the use of animal protein foods should consist of chicken, turkey, cornish hen and fish, and that all milk and yogurt products consumed are non-fat or 1% varieties. No cheese above 3% milk fat should be consumed and butter, ice cream, whipping cream, regular chocolate products, items containing coconut or palm oil, and deep fried products of all types, be avoided or greatly reduced. Increasing soluble dietary fiber intake can also reduce blood cholesterol levels by dragging cholesterol out of the body, as well as bile acids, which can serve as precursors (building block) to the synthesis of cholesterol in the liver. Soluble fiber is found in many fruits (especially apples, peaches, pairs, and plums) and vegetables, oat bran, psyllium husk fiber, ground flaxseeds, and in beans and peas. Remaining physically fit, aerobically, and at or near your ideal weight, are also important lifestyle factors in preventing heart attack and stroke in the postmenopausal years.

It should also be noted that soy products and soy extract supplements are known to reduce blood cholesterol levels by 9 – 12% in patients with high cholesterol levels. The same is true for a supplement known as gamma-oryzanol, which is derived from rice bran oil. Both soy extract and gamma-oryzanol have been shown to reduce hot flashes and other menopausal symptoms and are excellent alternative therapies to the use of HRT in postmenopausal women, as I will discuss shortly. Gamma-oryzanol is an approved drug for the management of menopausal symptoms in Japan, where the research on this natural agent has been performed. It is very convenient that soy extract and gamma-oryzanol can help reduce menopausal symptoms, reduce cholesterol levels, and in the case of soy isoflavones, also help to maintain bone mineral density.
Osteoporosis
The decline in estrogen levels that accompanies the menopausal years also permits calcium to leak out of bone into the blood stream, where it will eventually become filtered by the kidney and exit the body in the urine. This of course, leads to osteoporosis, which increases risk of fractures. Osteoporosis is reaching epidemic proportions in our society largely due to insufficient calcium intake and accumulation in bone, especially between ages 11 and 24, and loss of calcium from bone during the menopausal years. It should be noted that Canadian statistics indicate that complications from osteoporotic hip fractures (e.g., the development of pneumonia) result in more deaths each year than the combined mortality rate from breast and ovarian cancers. The lifestyle recipe to prevent osteoporosis during the menopausal years is as follows:
1.Ingest 1,500 mg per day of calcium, if not taking HRT. This can be through a combination of calcium from diet and supplements (note that calcium carbonate and calcium citrate are absorbed equally as well if taken with meals). As calcium carbonate is less expensive, it represents a more cost-effective intervention for patients. However, if the patient has had a previous history of kidney stones, calcium citrate may be preferred due to its greater solubility.
2.Supplement with 600 to 1,000 IU of Vitamin D. For general health reasons women should consider taking a high potency multiple vitamin and mineral, which normally includes 400 IU of Vitamin D. Studies show that postmenopausal women ingesting an additional 200 to 400 IU of Vitamin D per day may reduce their risk of hip fractures by approximately 50%. A high potency multiple vitamin and mineral (including extra antioxidant protection and a B-50 complex) contains other nutrients important to bone health (calcium zinc, magnesium, copper) as well as providing comprehensive micronutrient support for other aspects of health optimization. As we age, our kidneys reduce their ability to convert 25-hydroxyvitamin D to 1,25-dihydroxyvitamin D, which is twice as powerful a form of Vitamin D, than is 25-hydroxyvitamin D. However, studies indicate that by increasing blood levels of 25-hydroxyvitamin D, through the intake of Vitamin D supplements (600 – 1,000 IU per day), a postmenopausal women can compensate for the drop off in 1,25-hydroxyvitamin D synthesis, and thereby, significantly reduce her risk of osteoporotic fractures. Vitamin D is required for the absorption of calcium from the intestinal tract and promotes optimal bone mineral density in a number of ways.
3.Perform weight-bearing and/or resisted exercises 3 to 6 times per week. Weight bearing exercise such as walking or jogging, and weight training exercises, place increased stress on the spine and femurs, which respond by holding their calcium in bone to help withstand the physical stresses acting on the bone structures. Some studies reveal that postmenopausal women can increase their bone density, without using HRT, by simply ingesting more calcium and performing a series of 5 specific weight training exercises, twice per week. The five weight-training stations include hip extension, knee extension, abdominal machine, back extension machine, and lateral pull down machine. This protocol had each participant perform two sets of 10 repetitions at each station, at 80% of their maximal effort.
4.Supplement with a product that contains Black Cohosh and Soy Isoflavones. As will be discussed later, the standardized grade of Black Cohosh and Soy Extract have been shown to reduce menopausal symptoms and evidence exists to show that they can also help to preserve bone mineral density via their estrogenic effects on bone receptors.
Breast Cancer
It is well documented that women who are overweight during the postmenopausal years have approximately a three times greater risk of developing breast cancer. This is has been directly linked to the fact that as fat mass increases there is a greater conversion of the hormone androstenedione to estrone within the stromal tissue (supporting structure) of fat tissue. Higher circulating estrone hormone (one of three types of estrogens made by the female body) levels are associated with increased risk of breast cancer, as estrone is known to increase the cell division rate of breast cells. In turn, this leads to a greater chance of genetic mutations occurring, which may be cancerous. Once formed, estrone can be further converted into beta-estradiol, another powerful estrogen hormone that is associated with increased breast cancer risk. This is exactly the same mechanism through which HRT has been shown to increase breast cancer risk. Thus, postmenopausal women would be well advised to attain and maintain an ideal body weight and a body mass index below 25. The New York University Women’s Health Study showed that postmenopausal women with a body mass index higher than 24.87 had a three times greater risk of developing breast cancer within a 5-year follow up period than did postmenopausal women with a body mass index below 24.87. You can calculate your body mass index by dividing your weight (in kilograms) by your height (in meters) squared.
As well, avoiding the use of HRT is emerging as a significant strategy upon which to help prevent breast cancer in postmenopausal women.

Don’t have time to read the whole book right now?

No worries. Let me send you a copy so you can read it when it’s convenient for you. Just let me know where to send it.

SIGNAL TRANSDUCTION, KEY RECEPTORS AND APOPTOSIS MECHANISMS IN CANCER

Dr. James Meschino, 

DC, MS, ROHP

 REFERENCES

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Atalay G, Cardoso F, Awada A and. Piccart M. J Novel therapeutic strategies targeting the epidermal growth factor receptor (EGFR) family and its downstream effectors in breast cancer. Annals of Oncology 14:1346-1363, 2003
Carter P: Improving the efficacy of antibody-based cancer therapies. Nat Rev Cancer 2001;1:118-129

EGFR-Info.com. (2003). The epidermal growth factor as a clinical target in cancer. Retrieved October 4, 2003, from http://www.egfr-info.com

Gloss, G. (1995). WCLC conference highlights: Growing wealth of clinical experience with EGFR inhibitors. Signal, 4(3), 13–18.

Li E, Hristova K. Role of receptor tyrosine kinase transmembrane domains in cell signaling and human pathologies.. Biochemistry 45 (20): 6241-51. 2006.

Jackson, J. (n.d.). Specificity of ras signaling in breast cancer. Retrieved October 4, 2003, from http://www.cbcrp.org/research/PageGrant.asp?grant_id=1703

Karnes, W.E., Weller, S.G., Adjei, P.N., Kottke, T.J., Glenn, K.S., Gores G.J., et al. (1998). Inhibition of epidermal growth factor receptor kinase induces protease-dependent apoptosis in human colon cancer cells. Gastroenterology, 114, 930–939.

Lundberg, A.S., & Weinberg, R.A. (1999). Control of the cell cycle and apoptosis. European Journal of Cancer, 35, 1886–1894.

Poon, T.C.W., Chan A.T.C., To, K.F., Teo, P.M.L., Chan, M.L., Mo, K.F., et al. (2001). Expression and prognostic significance of epidermal growth factor receptor and HER2 protein in nasopharyngeal carcinoma [Abstract 913]. Proceedings of the American Society of Clinical Oncology, 20, 229a.

PhRMA Reports Identifies More than 400 Biotech Drugs in Development. Pharmaceutical Technology, August 24, 2006

Rinehart, J.J., Wilding, G., Willson, J., Krishnamurthi, S., Natale, R., Dasse, K.D., et al. (2003). A phase I clinical and pharmacokinetic (PK)/food effect study of oral CI-1033, a pan-erb B tyrosine kinase inhibitor, in patients with advanced solid tumors [Abstract 821]. Proceedings of the American Society of Clinical Oncology, 22, 205.

Salomon, D.S., Brandt, R., Ciardiello, F., & Normanno, N. (1995). Epidermal growth factor-related peptides and their receptors in human malignancies. Critical Reviews in Oncology and Hematology, 19, 183–232.

Wells, A. (1999). Molecules in focus EGF receptor. International Journal of Biochemistry and Cell Biology, 31, 637–643.


G. Atalay, F. Cardoso, A. Awada and M. J. Piccart Novel therapeutic strategies targeting the epidermal growth factor receptor (EGFR) family and its downstream effectors in breast cancer. Annals of Oncology 14:1346-1363, 2003
Thompson, CB. Apoptosis in the pathogenesis and treatment of disease. Science 267. 1995.

Oncogenes, Proto-oncogenes and Cancer
Oncogenes and Cancer - An oncogene is a modified gene, or a set of nucleotides that codes for a protein and is believed to cause cancer. Genetic mutations resulting in the activation of oncogenes increase the chance that a normal cell will develop into a tumor cell. Oncogenes are figuratively thought to be in a perpetual tug-of-war with tumor suppressor genes (e.g, p53 and p21 tumor suppressor genes), which act to prevent DNA damage and keep the cell's activities under control. There is much evidence to support the notion that loss of tumor suppressors or gain of oncogenes can lead to cancer. Oncogenes are mutant forms of normal functional genes (called proto-oncogenes) that have a role in normal cell proliferation. Oncogenes are found in tumours and in retroviruses; in the latter case, having been picked up along with retroviral genes during retroviral replication in the host. Once incorporated as part of the retroviral genome, they are activated at inappropriate times and places by retroviral promoters, thereby becoming oncogenes.
Proto-oncogenes - A proto-oncogene is a normal gene that can become an oncogene due to mutations or increased expression. Proto-oncogenes code for proteins that help to regulate cell growth and differentiation. Proto-oncogenes are often involved in signal transductionand execution of mitogenic signals, usually through their protein products. Upon activation, a proto-oncogene (or its product) becomes a tumor inducing agent, an oncogene. Examples of proto-oncogenes include RAS, WNT, MYC, and ERK. For instance, proteins in the Ras family are very important molecular switches for a wide variety of signal pathways that control such processes as cytoskeletal integrity, proliferation, cell adhesion, apoptosis, and cell migration. Ras and ras-related proteins are often deregulated in cancers, leading to increased invasion and metastasis, and decreased apoptosis. RAS activates a number of pathways but an especially important one seems to be the mitogen-activated protein (MAP) kinases, which themselves transmit signals downstream to other protein kinases and gene regulatory proteins.
The proto-oncogene can become an oncogene by a relatively small modification of its original function. There are three basic activation types:
1.A mutation within a proto-oncogene can cause a change in the protein structure, causing an increase in protein (enzyme) activity or a loss of regulation.
2.An increase in protein concentration, caused by
a.an increase of protein expression (through misregulation)
b.an increase of protein stability, prolonging its existence and thus its activity in the cell
c.a gene duplication (one type of chromosome abnormality), resulting in an increased amount of protein in the cell.
3.Mutations in microRNAs can lead to activation of oncogenes. Research indicates that small RNAs 21-25 nucleotides in length called microRNAs (miRNAs) can control expression of these genes by down-regulating them, a function that is lost with microRNA mutation.

References:
1.Yokota J Tumor progression and metastasis. Carcinogenesis. 21 (3): 497-503. 2000.
2. Todd R, Wong DT. Oncogenes. Anticancer Res. 19 (6A): 4729-46. 1999

Tumor Suppressor Genes
Tumor suppressor genes, or more precisely, the proteins for which they code either have a dampening or repressive effect on the regulation of the cell cycle or promote apoptosis, and sometimes do both. The functions of tumor suppressor proteins fall into several categories:
1.Repression of genes that are essential for the continuing of the cell cycle. If these genes are not expressed, the cell cycle will not continue, effectively inhibiting cell division.
2.Coupling the cell cycle to DNA damage. As long as there is damaged DNA in the cell, it should not divide. If the damage can be repaired, the cell cycle can continue.
3.If the damage can not be repaired, the cell should initiate apoptosis, or programmed cell death, to remove the threat it poses for the greater good of the organism.
4.Some proteins involved in cell adhesion prevent tumor cells from dispersing, block loss of contact inhibition, and inhibit metastasis.

References:
Sherr C. Principles of tumor suppression. Cell 116 (2): 235-46. 2004
Hirohashi S, Kanai Y. Cell adhesion system and human cancer morphogenesis. Cancer Sci 94 (7): 575-81. 2003

Understanding Receptors and Second Messengers In Signal Transduction Pathways Related To Cell Proliferation, Apoptosis and Cancer

PI3 Kinase (Phosphatidylinositol 3-Kinase) PI3K is responsible for phosphorylation of the 3 position of the inositol ring of PI(4,5)P2, to generate PI(3,4,5)P3, a potent second messenger required for survival signaling, and insulin action. PI3 Kinase is also activated by tyrosine kinase, Ras, and by the β:γ subunits of heterotrimeric G-proteins. .Akt is the major known effector of the PI3 Kinase pathway. Generation of PIP3 results in the activation of PDK1, which phosphorylates Akt.


Akt ​Akt phosphorylates Bad, resulting in protection from apoptosis. Bad, or "Bcl-2 antagonist of cell death" is member of the Bcl-2 family and an important regulator of life versus death. Unphosphorylated Bad dimerizes with Bcl-2 and Bcl-XL, neutralizing their anti-apoptotic activity. Activation of the PI 3-Kinase pathway leads to activation of Akt which phosphorylates Bad.

Apoptosis/survival is regulated by the relative balance of pro-apoptotic (Bax, BclXS, Bak, Bad, Bar) and anti-apoptotic (Bcl2, BclXL, Mcl-1, Dad-1) family members, and their heterodimerization. Bcl2 is phosphorylated by the ASK1/MKK7/JNK1 pathway on Ser70 during progression through the cell cycle; whether this up-or down-regulates the anti-apoptotic effect of Bcl2 remains controversial

Cytochome c Cytochrome c, released from the mitochondria, along with APAF1 complex in the cytosol activates caspase 9 as part of the apoptotic pathway. Bak (Bcl2 homologous Antagonist/Killer) is closely associated with this event. Bak is a member of the Bcl2 family of proteins that are involved in the regulation of programmed cell death. Other members include Bax, Bad, Bcl-x and Mcl-1. Bak is a proapoptotic protein which forms mitochondrial pores by oligomerization. Recent studies suggest that pore formation leads to cytochrome c efflux from the mitochondria. tBID, the truncated form of the proapoptotic protein BID, has been implicated in an allosteric activation of Bak, resulting in the Bak pore formation.


Apaf -1 Apaf-1 (apoptosis protease-activating factor 1) binds to cytochrome c and caspase-9 which leads to caspase-9 activation. The release of cytochrome c from the mitochondria provides a mechanism for apoptosis through Apaf-1-induced activation of caspases as well as necrosis due to the cessation of electron chain-transport. It has been proposed that Bcl-2 may interfere with the mitochondria-dependent apoptotic pathways at two points; preventing cytochrome c release from the mitochondria and directly interfering with Apaf-1.


Caspase Enzymes and Apoptosis  Caspase - Cysteine aspartyl proteases related to the C. elegans CED-3 death protein comprise the caspase family. All are expressed as proenzymes which are activated by proteolysis. With respect to their roles in apoptosis, Caspases can be subdivided into initiator (Caspases 8, 9, 10) and effector (Caspases 3, 6, 7) caspases, depending on whether they are activated by receptor clustering (initiator) or by mitochondrial permeability transition (effector).
Effector caspases, most notably Caspase 3, cleave numerous substrates to effect the morphological changes associated with apoptosis. The significance of PARP cleavage is not clear, but it is an excellent marker for caspase activation and the presumption of ongoing apoptosis.
Mitochondria play an essential role in the apoptotic pathway of many cells by releasing apoptogenic proteins into the cytosol. The Bax protein, which shares highly conserved domains with Bcl-2, can form ion-conducting channels in the lipid bilayers of mitochondria. Bax presents an interesting therapeutic target for many diseases involving apoptosis such as cancer or neurodegenerative disorders.
Mitochondrial proteins known as SMACs (second mitochondria-derived activator of caspases) are released into the cytosol following an increase in permeability. SMAC binds to inhibitor of apoptosis proteins (IAPs) and inhibits them, preventing the IAPs from arresting the apoptotic process and therefore allowing apoptosis to proceed. IAP also normally suppresses the activity of a group of caspases, which carry out the degradation of the cell, therefore the actual degradation enzymes can be seen to be indirectly regulated by mitochondrial permeability.
Cytochrome c is also released from mitochondria due to increased permeability of the outer mitochondrial membrane, and serves a regulatory function as it precedes morphological change associated with apoptosis. Once cytochrome c is released it binds with Apaf-1 and ATP, which then bind to pro-caspase-9 to create a protein complex known as an apoptosome. The apoptosome cleaves the pro-caspase to its active form of caspase-9, which in turn activates the effector caspase-3, ultimately causing apoptosis to occur.


PARP PARP - Poly(ADP-Ribose) Polymerase 1 (PARP-1), when activated by breaks in DNA, poly ADP-ribosylates nuclear proteins, resulting in NAD+ depletion and cell death by apoptosis. During apoptosis, Caspase 3 cleaves PARP into signature 85 and 24 kDa fragments. The 24 kDa fragment irreversibly binds to the broken ends of DNA, preventing access of repair enzymes to DNA, and ensuring the irreversibility of apoptosis. PARP cleavage is commonly used as a marker to "prove" cell death by apoptosis versus necrosis. Western blot detection of PARP cleavage (appearance of the 85 kDa fragment) is widely used as a readout of apoptosis.


Between 50 billion and 70 billion cells die each day due to apoptosis in the average human adult. For an average child between the ages of 8 to 14, approximately 20 billion to 30 billion cells die a day. In a year, this amounts to the proliferation and subsequent destruction of a mass of cells equal to an individual's body weight. Excessive apoptosis causes hypotrophy, such as in ischemic damage, whereas an insufficient amount results in uncontrolled cell proliferation, such as cancer.


Apoptosis can occur when a cell is damaged beyond repair, infected with a virus, or undergoing stress conditions such as starvation. DNA damage from ionizing radiation or toxic chemicals can also induce apoptosis via the actions of the tumour-suppressing gene p53. The "decision" for apoptosis can come from the cell itself, from the surrounding tissue, or from a cell that is part of the immune system. In these cases apoptosis functions to remove the damaged cell, preventing it from sapping further nutrients from the organism, or to prevent the spread of viral infection.


Apoptosis also plays a role in preventing cancer; if a cell is unable to undergo apoptosis, due to mutation or biochemical inhibition, it can continue dividing and develop into a tumour. For example, infection by papillomaviruses causes a viral gene to interfere with the cell's p53 protein, an important member of the apoptotic pathway. This interference in the apoptotic capability of the cell plays a critical role in the development of cervical cancer.


In the adult organism, the number of cells is kept relatively constant through cell death and division. Cells must be replaced when they become diseased or malfunctioning; but proliferation must be compensated by cell death. This balancing process is part of the homeostasis required by living organisms to maintain their internal states within certain limits.


The Immune System and Apoptosis  - Cytotoxic T-cells are able to directly induce apoptosis in cells by opening up pores in the target's membrane and releasing chemicals which bypass the normal apoptotic pathway. The pores are created by the action of secreted perforin, and the granules contain granzyme B, a serine protease which activates a variety of caspases which induce apoptosis. Interferon, sometimes used in cancer therapy, is a protein made by immune cells that upregulates the function of cytotoxic T- cells (natural killer cells), helping them stimulate apoptosis of cancer cells.


FADD Death Receptors  FADD (Fas-Associated, Death Domain) binds to the cytoplasmic portion of Fas, and recruits Caspase 8 to the Fas receptor. As such, it acts as an adapter protein to transduce apoptotic signals from receptor into the cell.


Fas Death Receptor  Fas is a receptor of the TNF Receptor family involved in initiation of apoptosis of lymphoid cells. Fas ligand binds to Fas and causes clustering of Fas molecules. Adapter proteins such as FADD recruit Caspase 8 to Fas, which becomes activated and induces the apoptotic cascade. IgM against Fas is also able to induce apoptosis by clustering of receptor molecules.


Effects of Insulin  Insulin action stimulates the PI3 Kinase pathway, resulting in Akt activation, which phosphorylates and inactivates Glycogen Synthase Kinase 3 (GSK3). Glycogen Synthase is then rapidly dephosphorylated, and activated

Glycogen Synthase Kinase 3 is active in the absence of the action of signaling pathways. The function of GSK3 is to phosphorylate Glycogen Synthase and thereby inactivate it


Tissue Necrosis Factor Receptors  Tissue Necrosis Factor Receptors (TNFRs), which are members of a superfamily of proteins known as Death Receptors, resulting in receptor aggregation and recruitment of adapters (i.e., TRAF [TNF Receptor-Associated Factor] proteins) to the intracellular portion of the complex. TNFR complex formation activates Caspase 8, the SAP Kinase pathway (dependent on recruitment of Daxx), and the NFκB pathway (which controls apoptosis versus proliferation


Insuling-like Growth Factor  Insulin-like Growth Factor - The IGFs are involved in skeletal growth, and are essential for prevention of apoptosis. Serum levels of free IGFs are kept low by the action of IGF binding proteins (IGFBPs), which sequester the IGFs. Overexpression of IGFBPs may induce apoptosis, presumably by reduction of free IGF; IGFBP levels are also altered in some cancers. The IGF-I Receptor is not as mitogenic as some other growth factor receptors, but its ability to activate the PI3 Kinase pathway, through the Insulin Receptor Substrate (IRS) proteins, is critical for mediating cell survival


Jun N- Kinase  The stress-activated protein kinase 1 family is also referred to as the jun N-terminal kinase family. The stress-activated kinases are only weakly activated by mitogenic stimuli, but potently activated by stress stimuli, such as inflammatory cytokines, ischemia, chemotherapeutic agents, and irradiation.


JNK/SAPK1 kinases  The JNK/SAPK1 kinases like the other MAPK-like kinases, are thought to phosphorylate multiple substrates and regulate many processes, including proliferation (in some cell types) and apoptosis.


SAPK2/3 family  The SAPK2/3 family is most widely referred to as the p38 family. These kinases are also activated by stresses, most notably inflammatory cytokines, irradiation, and certain toxins such as anisomycin, and arsenite. The activating kinases of SAPK2/3 are SKK2/MEK3 for SAPK2a and 2b, and MKK6 for SAPK3. The targets of the SAPK2/3 family include the MAPKAP kinases 2 and 3/3pK. In addition, SKK4 is related to this family, exhibiting 60% identity, and is activated by MKK6.


p53 gene tumor suppressor gene  The p53 gene is mutated in approximately half of all human cancers. It is involved in the cellular response to cytotoxic stresses, and together with p19ARF, induces expression of p21Cip1, to cause cell cycle arrest.
In addition, p53 is able to induce apoptosis, both by transcriptional and non-transcriptional mechanisms.


Nuclear Factor – kappa beta (NFκB)  NFκB signaling is a critical regulator not only of immune function, but also of proliferation versus apoptosis in response to various stimuli. It is regulated by an inhibitory protein, IκB. IκB has a nuclear localization sequence, as well as an export sequence. When in complex with NFκB, the NLS is inactive (perhaps masked), and the complex is cytoplasmic. When I&kapp;B is free, the NLS is active, and at least partially dominant to the export sequence. IκB thus shuttles to and from the nucleus, and maintains NFκB in the cytoplasm, preventing NFκB mediated transcription. Various stimuli lead to activation of IKK (IκB Kinase), which phosphorylates IκB on serines 32 and 36, marking it for ubiquitination and degradation. Once IκB is degraded, NFκB is able to initiate transcription. Mutant IκB in which serines 32 and 36 are changed to alanines, is not phosphorylated, and therefore not degraded. Cells expressing this protein are not able to activate NFκB, providing a useful tool to study the role of NFκB in various pathways and processes


Interleukins (ILs)  Interleukins constitute a broad family of cytokines, primarily of hematopoietic cell origin. IL-1, IL-6 and IL-8 are pro-inflammatory cytokines, IL-2 is a T-cell growth factor, while IL-7 is a B-cell growth factor. IL-15 shares many of its properties with IL-2. In fact, IL-2, IL-4, IL-7 and IL-15 signaling involves a common IL-2Rγ subunit, a common theme in immune cell signaling, where receptors are multi-component, and some components are shared between multiple receptors.


T-cell Receptor (TCR)  The T-cell Receptor is found on the surface of T-cells and is responsible for recognition of foreign antigen. Antigen binding to the TCR results in T-cell activation and proliferation (clonal selection). The TCR is composed of an α and a β subunit, either CD4 (on Th cells) or CD8 (on Tc cells), and CD3, which is made up of six subunits arranged into three dimers derived from five proteins (δ, ε, γ, ζ and η). The TCR initiates a signaling cascade that begins with the CD3 complex and proceeds through Lck to LAT and so on to Ras and then ERK, or through Fyn and ZAP-70 and so on to Rac and then JNK.


FAK (Focal Adhesion Kinase)  FAK is a tyrosine kinase which localizes to focal adhesions. It autophosphorylates on tyrosine during adhesion and spreading, and is thought to be a critical transducer of adhesion-dependent growth and survival. FAK is a substrate of Src, and phosphorylation of FAK may be the mechanism by which Src-transformed cells achieve adhesion-independent growth. FAK is not known to be overexpressed in human cancer, but the activation state of FAK in cancer has not been thoroughly addressed.


Vascular Endothelial Growth Factor (VEGF)  VEGF is a dimeric ligand, and is among the most potent angiogenic mitogens. VEGF is secreted by tumor cells and other cells exposed to hypoxia. Expression of VEGF is stimulated by FGF-2 (basic FGF), and it activates Flt-1 and KDR, the two high-affinity receptors for VEGF. The VEGF receptors stimulate the Ras-MAP kinase pathway, suggesting that it signals as a conventional receptor tyrosine kinase.


Raf  Raf, in addition to its role in mitogenesis, Raf-1 may play a role in regulation of apoptosis and cell cycle progression. Activation of Raf-1 involves phosphorylation of Ser338/339 and Tyr340/341. Activating mutations of B-Raf that disrupt its auto-inhibition loop have been implicated in a number of cancers, including melanoma and colon cancer. In these cases the raf pathway remains activated prompting increase cellular proliferation and inhibiting apoptosis.


Ras–Raf–MAPK pathway  Ras proteins control a wide variety of cellular processes including growth, differentiation, apoptosis and cytoskeletal organization. Ras proteins are activated in response to a wide variety of intracellular and extracellular stimuli. Activated Ras is rapidly converted to its guanosine diphosphate (GDP)-bound inactive state by hydrolysis of the bound guanosine triphosphate (GTP) by an intrinsic GTPase activity. This mechanism of inactivation is thought to be impaired in mutant Ras, which remains in the activated form and conveys uncontrolled proliferative signals continuously, despite the absence of stimulation. Ras proteins are mutationally activated in 30% of human cancers, including BC.
Ras can be activated by receptor TKs. Tyrosine phosphorylated receptors provide binding sites for the adaptor protein Grb2 (growth factor receptor-bound protein 2), which recruits Ras activator protein SOS (son-of-sevenless guanine nucleotide exchange factor).
Upon binding to Grb2, SOS mediates the activation of Ras by facilitating its switch from the inactive GDP-bound from to the GTP-bound active form. Then, GTP-bound Ras can activate several downstream effector pathways.
Raf-1, another protein kinase, is one of these effector molecules. It phosphorylates MEK1 (MAPK/Erk kinase) and MEK2, which in turn phosphorylate the MAPKs, ERK1 and -2 (extracellular signal-regulated kinases). Once activated, Erk1 and -2 translocate into the nucleus, where they phosphorylate a variety of substrates, including nuclear transcription factors, and ultimately lead to transcription of target genes associated with cellular proliferation.
Other substrates for Ras signaling include Rac/Rho (small GTP-binding proteins), PI3K and mitogen-activated protein kinase kinase (MEKK). The Rac–rho pathway is involved in cytoskeletal organization, the PI3K pathway is associated with cell survival, and the MEKK and MAPK pathways mediate cellular proliferation signals. The MAPK pathway is activated preferentially by mitogens, growth factors and tumor promoters, and the other downstream pathways mediated by Ras signaling are stimulated by inflammatory cytokines, hormones and various forms of stress stimuli.
MEKK activates another MAPK family member JNK (Jun N-terminal kinase) via SEK (stress-activated protein kinase), and the activation of this pathway is associated with apoptosis and/or proliferation depending on the dynamic balance between different signal transduction pathways.
JNK activates nuclear transcription factor c-Jun, a major component of activator protein-1 (AP-1). The other component of AP-1, c-fos, is activated by the MAPK pathway mediated through EGFR signaling. The generation of AP-1 is thought to play an important role in the development of endocrine resistance in breast cancer as one of the critical intersection points between estrogen receptor (ER) and EGFR signaling pathways. Many signal transduction pathways impinge on Ras-mediated signaling at different levels, so that the net effect of a given stimulus reflects merely the balance of crosstalk among these pathways.


PI3K–Akt pathway  The PI3K (phoshpatidylinositol phosphate) family of enzymes has been linked to many aspects of malignant transformation, including increased proliferation, growth, motility, invasiveness, metastases, angiogenesis and cell survival and represent a good target for biological therapies (monoclonal antibodies and/or small molecules). PI3K is activated by a diverse set of stimuli including cell surface receptors (G-protein-coupled receptors, receptors with TK activity), tyrosine phosphorylated proteins (e.g. insulin-regulated substrate, IRS) and small G proteins (e.g. Ras). EGFR (ErbB-1), in contrast to other members of the HER family of receptors, induces activation of the PI3K pathway relatively weakly, since this receptor has no intracellular binding sites for PI3K.
Upon activation, PI3K recruit several proteins to the cell membrane such as PKB also known as Akt (protein kinase B, also known as Akt), PDK1 (3-phosphoinositide-dependent protein kinase) and PDK2, small proteins of the Ras family, enabling these signaling proteins to come into close contact with their substrates. PKB/Akt, is thought to be the major player in the PI3K pathway; however, it can be activated by other molecules independent of the PI3K pathway, such as PKA (protein kinase A), the calmodulin-dependent kinase pathway, and cellular stresses like heat shock and hyperosmolarity. Among three Akt proteins, Akt2 and Akt3 were shown to be activated in human breast cancer samples.
The binding of PKB to PI3K is followed by its phosphorylation and activation by PDKs. Once activated, Akt regulates a number of proteins involved in the regulation of the cell cycle (cyclin D and E2F), apoptosis and cell survival [p21, p27, nuclear factor B (NF- B), Forkhead proteins, caspases and BAD]. Akt also phosphorylates a number of other proteins, the functions of which are closely related to breast cancer, such as BRCA1 and ER. It has been shown that alpha estrogen receptors can bind PI3K and activate PI3K/Akt pathway in an estrogen-independent manner.
Many other signal transduction pathways converge on the PI3K pathway at the level of Akt. For example, Ras activates the PI3K pathway, while Akt also regulates the activity of the Ras–Raf–MAPK pathway through phosphorylation and inactivation of Raf.
PI3K signaling can be inhibited by protein phosphatases, the prototype of which is the tumor suppressor gene product PTEN (phosphatase and tensin homolog deleted on chromosome 10).
Loss of PTEN activity due to either mutations or gene deletions is associated with malignancies such as Cowden’s syndrome. mTOR (mammalian target of rapamycin) kinases are among the downstream targets of Akt, and they are thought to link mitogenic stimulation to protein synthesis and cell cycle regulation. The inhibition of mTOR blocks the progression of the cell cycle at the G1 phase. Tumor cells without PTEN activity are considered to be more sensitive to mTOR inhibitors due to their increased level of Akt activity.


Transforming Growth Factor – Beta (TGF-β)  TGF-β is a multifunctional peptide that controls proliferation, differentiation, and other functions in many cell types. TGF-β acts synergistically with TGF-α in inducing cellular transformation. It also acts as a negative autocrine growth factor. Specific receptors for TGF-β activation trigger apoptosis when activated. Many cells synthesize TGF-β and almost all of them have specific receptors for this peptide.TGF-β1, TGF-β2, and TGF-β3 all function through the same receptor signaling systems.
TGF beta induces apoptosis in numerous cell types. TGF beta can induce apoptosis in two ways: The SMAD pathway or the DAXX pathway.
The SMAD pathway is the classical signaling pathway that TGF beta family members signal through. In this pathway TGF beta dimers binds to a type II receptor which recruits and phosphorylates a type I receptor. The type I receptor then recruits and phosphorylates a receptor regulated SMAD (R-SMAD). SMAD3, an R-SMAD, is implicated in inducing apoptosis. The R-SMAD then binds to the common SMAD (coSMAD) SMAD4 and forms a heteromeric complex. This complex then enters the cell nucleus where it activates the Mitogen-activated protein kinase 8 pathway. In turn, this triggers apoptosis.
In the DAXX pathway, TGF beta may also trigger apoptosis via the death associated protein 6 (DAXX adapter protein). DAXX has been shown to associate with and bind to the type II TGF beta receptor kinase.


The EGFR signaling pathway in Breast Cancer

The EGFR family of receptors is involved in the regulation of normal breast development. Preclinical data suggest that all compartments of EGFR signaling network including ligands, receptors and downstream effectors are implicated in the development and progression of breast cancer. Overexpression of HER-2 in transgenic mouse mammary glands has been shown to promote oncogenic transformation and development of malignant phenotype. In line with this data, HER-2 activation has been reported to increase metastatic/invasive potential and to induce progression of cell cycle by disrupting the delicate balance between cyclins and the endogenous CDK inhibitors in BC cell lines.


As such, HER-2 overexpression is associated with aggressive disease biology and reduced survival in breast cancer patients. These preclinical findings are further supported clinically by the success of trastuzumab, a monoclonal antibody against HER-2, which led to improved survival, longer time to progression, higher response rate and longer duration of response in breast cancer patients with HER-2 overexpressing tumors.


Numerous studies have also reported that EGFR (HER-1) overexpression is a poor prognostic factor in BC, often associated with advanced disease. HER-2 is overexpressed in 20–25% of breast tumors and is associated with a poor prognosis (The EGFR expression rate in breast cancer is in the range of 14–91%, depending on the method of assessment, and is almost always caused by increased receptor synthesis). While HER-2 overexpression is shown to be an early event in breast cancer development, HER-1 seems to be involved in later stages . The expression of both receptors is inversely correlated with the ER status of the tumor and HER-1/2 heterodimers have been shown to increase metastatic potential of breast cancer cell lines. Accumulating data suggest that EGFR and HER-2 also predict for a poor response to endocrine therapy, and that the mutual interaction between ER and growth factor pathways seems to hotwire the events inducing endocrine resistance in ER-positive breast tumors. Acquisition of resistance to endocrine therapy was shown to be associated with upregulation of EGFR signaling in breast cancer cell lines. ErbB receptors enhance ER signaling either by directly activating ER or through activation of MAPK and Akt. So far, preclinical data have shown that agents blocking HER-1 or HER-2 driven signaling pathways can restore hormone sensitivity in endocrine-resistant, HER-2 overexpressing breast tumors, delay the development of endocrine resistance and enhance the antiproliferative effect of endocrine agents.
These effects are partly mediated by the inhibition of downstream signaling cascades involved in the development of endocrine resistance. The expression of MAPK or Akt has been reported to predict a worse clinical outcome in patients treated with endocrine therapy. Both MAPK and Akt are capable of activating ER in a ligand independent manner, and activated MAPK can also enhance ER signaling by recruiting nuclear receptor co-activators.


The impact of EGFR downstream effectors on cell cycle progression may also indirectly mediate endocrine resistance. For example, Akt and MAPK phosphorylate the cell cycle inhibitor p27, which is required for the G1 arrest mediated by anti-estrogens. In addition, phosphorylation by MAPK leads to destabilization and proteasome-mediated degradation of p27 in breast cancer cell lines, therefore disturbing its inhibitory effect on cell cycle progression. Importantly, Akt-induced cytoplasmic sequestration of p27 in human breast cancer specimens has recently been shown to be associated with reduced patient survival.


Endogenous Akt, either constitutively activated via PTEN mutations and overexpression of ErbB receptors or induced by therapeutic agents, has been shown to promote breast cancer cell survival. Induction of Akt activity in response to commonly used therapeutic modalities in breast cancer is considered to be a potential mechanism of therapeutic resistance. In fact, inhibition of Akt by a targeted agent has been shown to potentiate trastuzumab-, doxorubicin-, paclitaxel- and tamoxifen-mediated apoptosis in BC cell lines.


EGFR signaling also seems to be vital for the survival of ER-negative breast cancer. Akt-3 is overexpressed in ER-negative breast cell lines and in tissue samples taken from patients. In addition, EGF-induced activation of PKC (one of the downstream substrates of PI3K) and NF- B (nuclear factor – kappa beta) has been shown to mediate cellular proliferation in ER-negative BC cells.


Regarding the other receptors of the EGFR family, HER-3, the kinase deficient member, has also been shown to be expressed in breast cancer, while the expression of HER-4 is uncommon in breast carcinomas compared with normal breast epithelium and is associated with favorable prognostic factors . Of note, HER-2/HER-3 heterodimers have the highest mitogenic potential and are constitutively activated in breast cancer cells with HER-2 gene amplification.


Consequently, all these data render the EGFR family of receptors, their ligands and their downstream effectors rational targets for the development of novel antitumor strategies in breast cancer. (To this end natural substances such as curcumin represent interesting prophylactic measures in the prevention of breast cancer, as curcumin has been shown to be a pan Erb inhibitor, in that it induces inhibition of all EGFR receptors (1-4)). 


Some New Targeted Biological Therapies In Cancer Treatment and Prevention Based On Signal Transduction Pathways


Tyrosine kinase inhibitors  Another mechanism by which one can target HER-2 is the inhibition of its TK activity. The safety, tolerability and pharmacokinetics of a new selective HER-2 tyrosine kinase inhibitor (TKI), TAK-165, is currently being evaluated in a multicenter phase I trial in HER-2 expressing breast cancer patients.


Curcumin and emodin Inhibit HER-2 and Tyrosine Kinase and Enhance Effects of Chemotherpy DrugsAnother mechanism by which one can target HER-2 is the inhibition of its TK activity. The safety, tolerability and pharmacokinetics of a new selective HER-2 tyrosine kinase inhibitor (TKI), TAK-165, is currently being evaluated in a multicenter phase I trial in HER-2 expressing breast cancer patients.


Heat Shock Protein Inhibitors  Heat shock proteins have emerged as attractive targets for new anticancer drugs because these molecules modulate the signal transduction pathways controlling tumor cell growth and survival. These molecules are not mutated in cancer, but they facilitate malignant transformation by enhancing the activity of many oncogenic growth factor receptors, kinases and transcription factors. Heat Shock Protein 90 (HSP90) is required for the refolding of proteins in response to environmental stress and the conformational maturation of several signaling proteins. The function of Heat Shock Proteins can be inhibited by certain compounds, such as 17-AAG (17-allylamino-17-demathoxygeldanamycin), which is currently in phase I clinical trials in advanced cancer patients. HER-2 TK is one of the most sensitive targets for HSP90 inhibitors.


Ligand-based strategies  Toxin conjugated ligands are generated by conjugating a potent cellular toxin with one of the ligands of the HER family receptor. For example, the TGF- –pseudomonas exotoxin A conjugate has been evaluated in a phase I trial. The toxins conjugated to the ligand can destroy the receptor bringing about decreased concentrations of specific receptors on the cell surface and thus, down-regulating signal transduction from this class of receptors.
Agents targeting RAS–RAF–MAPK pathway - In approximately 30% of human cancers, mutated Ras genes produce abnormal proteins that remain locked in the activated state, thereby relaying uncontrolled proliferative signals. Ras mutations are not common in BC (<5%). However, the fact that Ras can be activated by multiple stimuli, including EGFR family TKs, renders Ras a promising therapeutic target in breast cancer and other cancers. Only a few agents targeting the Ras–Raf–MAPK pathway are in clinical stages of development in breast cancer, but many of these agents are in the late phases of clinical development in other cancer types


Targeting Ras. Farnesyl transferase (FTase)  Activation of this pathway catalyzes a critical step in Ras activation and represents an important target for drug development. However, the initial early clinical studies with farnesyl transferase inhibitors (FTIs) focusing on colorectal cancer (CRC), non small cell lung cancer (NSCLC) and pancreatic cancers, known to have a high incidence of K-ras mutations, did not satisfy the high expectations of therapeutic success.


Targeting MEK  

CI 1040 (PD 1843220), a small molecule MEK inhibitor, has shown low toxicity and moderate efficacy in phase I trials. Based on this promising phase I data, this agent is moving into phase II clinical trials.


Agents targeting PI3K/Akt pathway - Targeting mTOR. The mTOR pathway is a key growth factor-mediated signal transduction pathway that regulates cell growth, closely related to the PI3K/Akt pathway. mTOR-dependent growth factor signaling include estrogen, HER-2/neu and IGF-1, all of which can be inhibited by mTOR inhibition, resulting in G1 arrest of the cell cycle. CCI-779 is an m-TOR inhibitor with activity seen in breast cancer cells, both in vitro and in vivo, and is the only agent of this category in later stages of clinical development in breast cancer. Side-effects were generally mild and the most frequently occurring grade 3–4 toxicities were asthenia, depression, g glutamyl transpeptidase increase, hypercholestrolemia, leucopenia, mucositis and somnolence. Based on this preliminary clinical activity, further evaluation of this agent in combination with other treatment modalities is planned in breast cancer patients


Targeting Akt  17-AAG, an indirect inhibitor of Akt activity, is an ansamycin antibiotic which has shown antitumor effects in HER-2-overexpressing breast cancer cell lines in several preclinical experiments. It inhibits the chaperone function of Heat Shock Protein 90, which in turn depletes several key signaling proteins involved in cell cycle control, hormone signaling and growth factor pathways, including HER-2, Akt and Raf-1. The preliminary findings from phase I trials in advanced cancer patients reported disease stabilization with acceptable toxicity.


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SIGNAL TRANSDUCTION, KEY RECEPTORS AND APOPTOSIS MECHANISMS IN CANCER

Dr. James Meschino, 

DC, MS, ROHP

Global Integrative Medicine Academy

The Global Integrative Medicine Academy was created to satisfy a need, expressed by many health professionals, to establish credentials as experts in Nutritional Medicine. But, health professionals also needed to be able to complete the programme with a minimum impact on their career, family, and lifestyle. That is why the Advanced Nutritional Medicine and Sports Nutrition Certification Program was created.

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