Life Extension Final Clerance Sale

Life Extension Magazine

LE Magazine Special Edition, Winter 2005/2006

Does PSA Promote Prostate Cancer?

by William Faloon
Reviewed and critiqued by Stephen B. Strum, MD, FACP

Lycopene Reduces Prostate Cell DNA Damage

Because cancer is initiated and promoted as the result of ongoing DNA damage, researchers conducted a study to evaluate the genomic effects of lycopene in men with localized disease. For three weeks, a group of 32 men consumed tomato sauce each day supplying 30 mg of lycopene. Prostate tissue was obtained initially at biopsy and then again after surgical removal of the prostate gland.38 After three weeks, PSA levels declined by 17.5% and a blood marker of DNA damage fell by 21.3%. An analysis of the prostate tissues showed that the lycopene-supplemented patients had major reductions in many of the DNA factors that usually favor uncontrolled prostate cancer cell propagation. Moreover, in the lycopene-supplemented patients, prostate cancer cells as well as hyperplastic prostatic tissue showed an increase in apoptosis (programmed cell death). This study showed that prostate cells readily take up lycopene, with cellular lycopene levels increasing 2.92-fold after only three weeks. This increase in lycopene correlated with a significant reduction of DNA damage in prostate tissue.38

Boron Shrinks Prostate Tumors, Reduces PSA in Mice

As noted earlier, most doctors regard PSA solely as a useful laboratory marker for diagnosing prostate cancer. At a cellular level, however, PSA functions as an active growth factor in the prostate gland. One such mechanism involves PSA’s enzymatic ability to degrade extracellular matrix (structural support) proteins such as fibronectin and laminin.1 This action of PSA may promote tumor growth and metastasis. Another potential tumor-promoting action of PSA involves freeing insulin-like growth factor 1 (IGF-1) from its binding protein (BP-3), providing increased local levels of IGF-1, leading to tumor growth.2,3 To understand the nature of our enemy—the cancer cell—we must realize that the tumor cell is functional and produces cell products that favor its growth, invasiveness, and spread!

Studies by Gallardo-Williams and colleagues have shown that boric acid and boronic acid significantly inhibit the degradation of fibronectin by enzymatically active PSA.1 In another study in mice the same authors used immunohistochemistry staining of tissues to show that expression of IGF-1 in tumors was markedly reduced by boric acid. In response to both low- and high-dose boron supplementation, PSA levels plummeted by an average of 87%, while tumor size declined by 31.5% on average. Also noted was a significantly lower incidence of mitotic figures in the boron-supplemented groups. Mitotic figures reflect DNA synthesis and proliferative activity.39

Consistent with these findings, a recent study showed that boron inhibited the proliferation of prostate cancer cell lines DU-145 (an androgen-independent line) and LNCaP (an androgen-dependent cell line) in a dose-dependent manner.40 These animal and cell line studies appear to be relevant to humans, based on a report from UCLA in which Cui and colleagues showed that men with the highest dietary boron intake reduced their prostate cancer risk by 54% compared to men with the lowest boron intake!12 While the authors noted that the observed association should be interpreted with caution because of the small case sample size and the nature of the cross-sectional study design, clearly these findings deserve further investigation. If the above-cited animal studies can be replicated in human patients, boron at doses ranging from 6 to 15 mg a day may become an effective and very low-cost adjuvant therapy.12

Curcumin Induces Cancer Cell Suicide

Cancer cells do not follow normal, healthy cell suicide programs. Old cells need to die and be discarded, but cancer cells proliferate and grow.

Numerous studies over the past two years have identified specific mechanisms by which curcumin inhibits the growth of prostate cancer cells and then activates genes that tell cancer cells to self-destruct (also referred to as apoptosis).41,42 One study showed that curcumin reprograms prostate cancer cells so as to make them less likely to metastasize to the bone, while another study demonstrated that curcumin has radiation-sensitizing effects, making cancer cells more vulnerable to destruction by conventional radiation therapy.43,44 The research on curcumin is so promising that pharmaceutical companies are currently developing curcumin analogs that can be patented as anti-cancer therapies.45,46

Critical Importance of Annual PSA Testing

In 2004, the New England Journal of Medicine published an article indicating that the rate of increase in PSA is a more important predictor of mortality than the PSA reading itself. Men who showed a 2.0 ng/ml or greater increase in PSA from the previous year’s level were 10 times more likely to die within seven years.47 The researchers recommended that men over the age of 35 should have a baseline PSA reading and then retest each year to measure the rate of increase (PSA velocity). A sharp rise in PSA mandates the need for more comprehensive evaluation and treatment. Without previous PSA readings, it is impossible for your doctor to calculate PSA velocity. Optimal measurement of PSA velocity requires at least three PSA readings, with each obtained at least six months apart and tested at the same laboratory using the same PSA laboratory procedure.

In summary, accumulating data suggest that PSA is no longer merely a laboratory test of prostate gland activity. Instead, PSA is recognized as a functional protein: an enzyme that may facilitate prostate cancer cell proliferation, invasion, and metastasis. Taking steps to suppress PSA may reduce prostate cancer risk and progression. Meaningful reductions in PSA, as demonstrated in many of the studies cited in this article, appear achievable by using natural supplements like lycopene, soy, green tea, and boron, as well as through prescription drugs such as Avodart® or Proscar®, which normally reduce serum PSA levels by 40-50%.48-50

Low-Cost Blood Testing

A number of blood tests can identify correctable risk factors before clinically advanced disease becomes established. Most people test their blood to ascertain levels of cardiovascular disease markers such as homocysteine, C-reactive protein, LDL (low-density lipoprotein), and HDL (high-density lipoprotein).

While the PSA test has become well known, some men have been reluctant to have it done for fear that it will reveal a problem that cannot be easily corrected. Over the past few years, however, a significant number of publications have revealed safe methods of lowering PSA and potentially reducing prostate cancer risk.

Life Extension members can obtain comprehensive blood test panels at discounted prices. The popular Male Panel includes the PSA test, along with homocysteine, DHEA , C-reactive protein, and numerous other tests. It does not, however, include the dihydrotestosterone (DHT) test that would be of significant importance if PSA levels were in any way elevated.

High DHT levels stimulate the androgen receptor to induce greater PSA production.51 DHT also interacts with extracellular tissues to increase prostate cancer cell mobility.52 These and other findings may well be the basis for the reduction in prostate cancer development seen in men treated with inhibitors of DHT. The normal retail price for the DHT test is $60, but members pay only $45.00 for this test.

More than ever before, determining your PSA (and DHT) levels may dramatically reduce your odds of becoming a prostate cancer victim.

References

1. Gallardo-Williams MT, Maronpot RR, Wine RN, et al. Inhibition of the enzymatic activity of prostate-specific antigen by boric acid and 3-nitrophenyl boronic acid. Prostate. 2003 Jan 1;54(1):44-9.

2. Cohen P, Graves HC, Peehl DM, et al. Prostate-specific antigen (PSA) is an insulin-like growth factor binding protein-3 protease found in seminal plasma. J Clin Endocrinol Metab. 1992 Oct;75(4):1046-53.

3. Cohen P, Peehl DM, Graves HC, et al. Biological effects of prostate specific antigen as an insulin-like growth factor binding protein-3 protease. J Endocrinol. 1994 Sep;142(3):407-15.

4. Giovannucci E, Ascherio A, Rimm EB, et al. Intake of carotenoids and retinol in relation to risk of prostate cancer. J Natl Cancer Inst. 1995 Dec 6;87(23):1767-76.

5. Heinonen OP, Albanes D, Virtamo J, et al. Prostate cancer and supplementation with alpha-tocopherol and beta-carotene: incidence and mortality in a controlled trial. J Natl Cancer Inst. 1998 Mar 18;90(6):440-6.

6. Helzlsouer KJ, Huang HY, Alberg AJ, et al. Association between alpha-tocopherol, gamma-tocopherol, selenium, and subsequent prostate cancer. J Natl Cancer Inst. 2000 Dec 20;92(24):2018-23.

7. Giovannucci E. A review of epidemiologic studies of tomatoes, lycopene, and prostate cancer. Exp Biol Med (Maywood.). 2002 Nov;227(10):852-9.

8. Giovannucci E, Rimm EB, Liu Y et al. A prospective study of tomato products, lycopene, and prostate cancer risk. J Natl Cancer Inst. 2002 Mar 6;94(5):391-8.

9. Lee MM, Gomez SL, Chang JS, et al. Soy and isoflavone consumption in relation to prostate cancer risk in China. Cancer Epidemiol Biomarkers Prev. 2003 Jul;12(7):665-8.

10. Jian L, Xie LP, Lee AH et al. Protective effect of green tea against prostate cancer: a case-control study in southeast China. Int J Cancer. 2004 Jan 1;108(1):130-5.

11. Leitzmann MF, Stampfer MJ, Michaud DS, et al. Dietary intake of n-3 and n-6 fatty acids and the risk of prostate cancer. Am J Clin Nutr. 2004 Jul;80(1):204-16.

12. Cui Y, Winton MI, Zhang ZF, et al. Dietary boron intake and prostate cancer risk. Oncol Rep. 2004 Apr;11(4):887-92.

13. Ansari MS, Gupta NP. A comparison of lycopene and orchidectomy vs orchidectomy alone in the management of advanced prostate cancer. BJU Int. 2003 Sep;92(4):375-8.

14. Ansari MS, Gupta NP. Lycopene: a novel drug therapy in hormone refractory metastatic prostate cancer. Urol Oncol. 2004 Sep;22(5):415-20.

15. Thiel R, Effert P. Primary adenocarcinoma of the seminal vesicles. J Urol. 2002 Nov;168(5):1891-6.

16. Holund B. Latent prostatic cancer in a consecutive autopsy series. Scand J Urol Nephrol. 1980;14(1):29-35.

17. Sakr WA, Haas GP, Cassin BF et al. The frequency of carcinoma and intraepithelial neoplasia of the prostate in young male patients. J Urol. 1993 Aug;150(2 Pt 1):379-85.

18. Geller J, Sionit L. Castration-like effects on the human prostate of a 5 alpha-reductase inhibitor, finasteride. J Cell Biochem Suppl. 1992;16H:109-12.

19. Deslypere JP, Young M, Wilson JD et al. Testosterone and 5 alpha-dihydrotestosterone interact differently with the androgen receptor to enhance transcription of the MMTV-CAT reporter gene. Mol Cell Endocrinol. 1992 Oct;88(1-3):15-22.

20. Wright AS, Thomas LN, Douglas RC et al. Relative potency of testosterone and dihydrotestosterone in preventing atrophy and apoptosis in the prostate of the castrated rat. J Clin Invest. 1996 Dec 1;98(11):2558-63.

21. Andriole GL, Humphrey P, Ray P, et al. Effect of the dual 5alpha-reductase inhibitor dutasteride on markers of tumor regression in prostate cancer. J Urol. 2004 Sep; 172(3):915-9.

22. Lazier CB, Thomas LN, Douglas RC et al. Dutasteride, the dual 5alpha-reductase inhibitor, inhibits androgen action and promotes cell death in the LNCaP prostate cancer cell line. Prostate. 2004 Feb 1;58(2):130-44.

23. Andriole GL, Roehrborn C, Schulman C, et al. Effect of dutasteride on the detection of prostate cancer in men with benign prostatic hyperplasia. Urology. 2004 Sep;64(3):537-41.

24. Thompson IM, Goodman PJ, Tangen CM, et al. The influence of finasteride on the development of prostate cancer. N Engl J Med. 2003 Jul 17;349(3):215-24.

25. Pezzato E, Sartor L, Dell’Aica I, et al. Prostate carcinoma and green tea: PSA-triggered basement membrane degradation and MMP-2 activation are inhibited by (-)epigallocatechin-3-gallate. Int J Cancer. 2004 Dec 10;112(5):787-92.

26. Sonoda T, Nagata Y, Mori M, et al. A case-control study of diet and prostate cancer in Japan: possible protective effect of traditional Japanese diet. Cancer Sci. 2004 Mar;95(3):238-42.

27. Dalais FS, Meliala A, Wattanapenpaiboon N, et al. Effects of a diet rich in phytoestrogens on prostate-specific antigen and sex hormones in men diagnosed with prostate cancer. Urology. 2004 Sep;64(3):510-5.

28. Partin AW, Pound CR, Clemens JQ, et al. Serum PSA after anatomic radical prostatectomy. The Johns Hopkins experience after 10 years. Urol Clin North Am. 1993 Nov;20(4):713-25.

29. Pound CR, Partin AW, Epstein JI et al. Prostate-specific antigen after anatomic radical retropubic prostatectomy. Patterns of recurrence and cancer control. Urol Clin North Am. 1997 May;24(2):395-406.

30. Hanlon AL, Hanks GE. Failure patterns and hazard rates for failure suggest the cure of prostate cancer by external beam radiation. Urology. 2000 May;55(5):725-9.

31. Han M, Partin AW, Pound CR et al. Long-term biochemical disease-free and cancer-specific survival following anatomic radical retropubic prostatectomy. The 15-year Johns Hopkins experience. Urol Clin North Am. 2001 Aug;28(3):555-65.

32. Hanks GE, Hanlon AL, Epstein B et al. Dose response in prostate cancer with 8-12 years’ follow-up. Int J Radiat Oncol Biol Phys. 2002 Oct 1;54(2):427-35.

33. Kupelian PA, Potters L, Khuntia D, et al. Radical prostatectomy, external beam radiotherapy <72 Gy, external beam radiotherapy > or =72 Gy, permanent seed implantation, or combined seeds/external beam radiotherapy for stage T1-T2 prostate cancer. Int J Radiat Oncol Biol Phys. 2004 Jan 1;58(1):25-33.

34. Jones EC, McNeal J, Bruchovsky N et al. DNA content in prostatic adenocarcinoma. A flow cytometry study of the predictive value of aneuploidy for tumor volume, percentage Gleason grade 4 and 5, and lymph node metastases. Cancer. 1990 Aug 15;66(4):752-7.

35. Deitch AD, Miller GJ, deVere White RW. Significance of abnormal diploid DNA histograms in localized prostate cancer and adjacent benign prostatic tissue. Cancer. 1993 Sep 1;72(5):1692-700

36. Perlman EJ, Epstein JI, Long PP et al. Cytogenetic and ploidy analysis of prostatic adenocarcinoma. Mod Pathol. 1993 May;6(3):348-52.

37. Shankey TV, Jin JK, Dougherty S, et al. DNA ploidy and proliferation heterogeneity in human prostate cancers. Cytometry. 1995 Sep 1;21(1):30-9.

38. Bowen P, Chen L, Stacewicz-Sapuntzakis M, et al. Tomato sauce supplementation and prostate cancer: lycopene accumulation and modulation of biomarkers of carcinogenesis. Exp Biol Med (Maywood). 2002 Nov;227(10):886-93.

39. Gallardo-Williams MT, Chapin RE, King PE, et al. Boron supplementation inhibits the growth and local expression of IGF-1 in human prostate adenocarcinoma (LNCaP) tumors in nude mice. Toxicol Pathol. 2004 Jan;32(1):73-8.

40. Barranco WT, Eckhert CD. Boric acid inhibits human prostate cancer cell proliferation. Cancer Lett. 2004 Dec 8;216(1):21-9.

41. Deeb D, Xu YX, Jiang H, et al. Curcumin (diferuloyl-methane) enhances tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis in LNCaP prostate cancer cells. Mol Cancer Ther. 2003 Jan;2(1):95-103.

42. Deeb D, Jiang H, Gao X, et al. Curcumin sensitizes prostate cancer cells to tumor necrosis factor-related apoptosis-inducing ligand/Apo2L by inhibiting nuclear factor-kappaB through suppression of IkappaBalpha phosphorylation. Mol Cancer Ther. 2004 Jul;3(7):803-12.

43. Chendil D, Ranga RS, Meigooni D et al. Curcumin confers radiosensitizing effect in prostate cancer cell line PC-3. Oncogene. 2004 Feb 26;23(8):1599-607.

44. Dorai T, Dutcher JP, Dempster DW et al. Therapeutic potential of curcumin in prostate cancer—V: Interference with the osteomimetic properties of hormone refractory C4-2B prostate cancer cells. Prostate. 2004 Jun 15;60(1):1-17.

45. Adams BK, Ferstl EM, Davis MC, et al. Synthesis and biological evaluation of novel curcumin analogs as anti-cancer and anti-angiogenesis agents. Bioorg Med Chem. 2004 Jul 15;12(14):3871-83.

46. Adams BK, Cai J, Armstrong J, et al. EF24, a novel synthetic curcumin analog, induces apoptosis in cancer cells via a redox-dependent mechanism. Anticancer Drugs. 2005 Mar;16(3):263-75.

47. D’Amico AV, Chen MH, Roehl KA et al. Preoperative PSA velocity and the risk of death from prostate cancer after radical prostatectomy. N Engl J Med. 2004 Jul 8;351(2):125-35.

48. Cote RJ, Skinner EC, Salem CE, et al. The effect of finasteride on the prostate gland in men with elevated serum prostate-specific antigen levels. Br J Cancer. 1998 Aug;78(3):413-8.

49. Andriole GL, Kirby R. Safety and tolerability of the dual 5alpha-reductase inhibitor dutasteride in the treatment of benign prostatic hyperplasia. Eur Urol. 2003 Jul;44(1):82-8.

50. Lowe FC, McConnell JD, Hudson PB, et al. Long-term 6-year experience with finasteride in patients with benign prostatic hyperplasia. Urology. 2003 Apr;61(4):791-6.

51. Lee C, Sutkowski DM, Sensibar JA, et al. Regulation of proliferation and production of prostate-specific antigen in androgen-sensitive prostatic cancer cells, LNCaP, by dihydrotestosterone. Endocrinology. 1995 Feb;136(2):796-803.

52. Murphy BC, Pienta KJ, Coffey DS. Effects of extracellular matrix components and dihydrotestosterone on the structure and function of human prostate cancer cells. Prostate. 1992;20(1):29-41.