Молекулярные мишени тамоксифена, отличные от эстрогеновых рецепторов

Экспериментальные работы, раскрывающие всё новые и новые биологические эффекты воздействия тамоксифена на опухолевые клетки как экспрессирующие, так и неэкспрессирующие эстрогеновые рецепторы, позволяют по-новому взглянуть на, казалось бы, хорошо известный препарат. В обзоре описаны мишени тамоксифена, блокирование которых вызывает ингибирование роста опухолевых клеток и процесса ангиогенеза, стимулирование программированной смерти клеток (апоптоза, аутофагии и некроза), ингибирование механизма множественной лекарственной резистентности, торможение инвазии и метастазирования. Так как во всех случаях последствия взаимодействия тамоксифена с клетками являются прогностически благоприятными, как с точки зрения торможения роста опухоли и её метастазирования, так и с точки зрения чувствительности к лекарственной терапии, авторы рассматривают это как чрезвычайно важное «добавление» к антиэстрогенному эффекту тамоксифена. Приведены аргументы, которые позволяют считать стратегию длительной адъювантной терапии тамоксифеном, созданную ещё в 70 годах XX века профессором Craig V. Jordan для лечения рака молочной железы с позитивным статусом эстрогеновых рецепторов, применимой и для других опухолей. Это, прежде всего, описанный в последние годы факт экспрессии в солидных опухолях практически всех известных локализаций и гистологических типов эстрогеновых рецепторов бета, которые также являются мишенью тамоксифена. Авторы считают, что для полной реализации всех сторон биологической активности тамоксифена при длительной адъювантной терапии злокачественных новообразований разных локализаций, помимо оценки эстрогеновых рецепторов, необходим молекулярно-биологический отбор больных с учётом экспрессии других клеточных мишеней антиэстрогена.

тамоксифен, апоптоз, ангиогенез, метастазирование, множественная лекарственная резистентность

1. Jordan V.C. Tamoxifen: catalyst for the change to targeted therapy. Eur J Cancer 2008; 44: 1: 30-38.

2. Obiorah I., Jordan V.C. Progress in endocrine approaches to the treatment and prevention of breast cancer. Maturitas 2011; 70: 4: 315-321.

3. Rohlff C., Blagosklonny M.V., Kyle E. et al. Prostate cancer cell growth inhibition by tamoxifen is associated with inhibition of protein kinase C and induction of p21(waf1/cip1). Prostate 1998; 37: 1: 51-59.

4. Cheng A.L., Chuang S.E., Fine R.L. et al. Inhibition of the membrane translocation and activation of protein kinase C, and potentiation of doxorubicin-induced apoptosis of hepatocellular carcinoma cells by tamoxifen. Biochem Pharmacol 1998; 55: 4: 523-531.

5. Sharif T.R., Sharif M. A novel approach for examining the anti-proliferative effect of protein kinase C inhibitors against human astrocytoma cells. Int J Oncol 1998; 13: 4: 685-692.

6. Chen T.C., Su S., Fry D., Liebes L. Combination therapy with irinotecan and protein kinase C inhibitors in malignant glioma. Cancer 2003; 97: 9: 2363-2373.

7. Lavie Y., Zhang Z.C., Cao H.T. et al. Tamoxifen induces selective membrane association of protein kinase C epsilon in MCF-7 human breast cancer cells. Int J Cancer 1998; 77: 6: 928-932.

8. Wang X.Y., Wang Y., Liu H.C. Tamoxifen lowers the MMP-9/TIMP-1 ratio and inhibits the invasion capacity of ER-positive non-small cell lung cancer cells. Biomed Pharmacother 2011; 65: 7: 525-528.

9. Fang Y.J., Pan Z.Z., Li L.R. et al. MMP7 expression regulated by endocrine therapy in ERbeta-positive colon cancer cells. J Exp Clin Cancer Res 2009; 28: 132.

10. Hoelting T., Siperstein A.E., Duh Q.Y., Clark O.H. Tamoxifen inhibits growth, migration, and invasion of human follicular and papillary thyroid cancer cells in vitro and in vivo. J Clin Endocrinol Metab 1995; 80: 1: 308-313.

11. Matsuoka H., Tsubaki M., Yamazoe Y. et al. Tamoxifen inhibits tumor cell invasion and metastasis in mouse melanoma through suppression of PKC/MEK/ERK and PKC/PI3K/Akt pathways. Exp Cell Res 2009; 315: 12: 2022-2032.

12. Xing R.H., Mazar A., Henkin J., Rabbani S.A. Prevention of breast cancer growth, invasion, and metastasis by antiestrogen tamoxifen alone or in combination with urokinase inhibitor B-428. Cancer Res 1997; 57: 16: 3585-3593.

13. Ahn S.J., Yoon M.S., Hyuk S. et al. Phospholipase C-protein kinase C mediated phospholipase D activation pathway is involved in tamoxifen induced apoptosis. J Cell Biochem 2003; 89: 3: 520-528.

14. Thiantanawat A., Long B.J., Brodie A.M. Signaling pathways of apoptosis activated by aromatase inhibitors and antiestrogens. Cancer Res 2003; 63: 22: 8037-8050.

15. Feng Y., Huang J., Ding Y. et al. Tamoxifen-induced apoptosis of rat C6 glioma cells via PI3K/Akt, JNK and ERK activation. Oncol Rep 2010; 24: 6: 1561-1567.

16. Moodbidri M.S., Shirsat N.V. Activated JNK brings about accelerated apoptosis of Bcl-2-overexpressing C6 glioma cells on treatment with tamoxifen. J Neurochem 2005; 92: 1: 1-9.

17. Zhang G.J., Kimijima I., Onda M. et al. Tamoxifen-induced apoptosis in breast cancer cells relates to down-regulation of bcl-2, but not bax and bcl-X(L), without alteration of p53 protein levels. Clin Cancer Res 1999; 5: 10: 2971-2977.

18. Hawkin R.A., Arends M.J., Ritchie A.A. et al. Tamoxifen increases apoptosis but does not influence markers of proliferation in an MCF-7 xenograft model of breast cancer. Breast 2000; 9: 2: 96-106.

19. Salami S., Karami-Tehrani F. Biochemical studies of apoptosis induced by tamoxifen in estrogen receptor positive and negative breast cancer cell lines. Clin Biochem 2003; 36: 4: 247-253.

20. Han P., Kang J.H., Li H.L. et al. Antiproliferation and apoptosis induced by tamoxifen in human bile duct carcinoma QBC939 cells via upregulated p53 expression. Biochem Biophys Res Commun 2009; 385: 2: 251-256.

21. Nazarewicz R.R., Zenebe W.J., Parihar A. et al. Tamoxifen induces oxidative stress and mitochondrial apoptosis via stimulating mitochondrial nitric oxide synthas. Cancer Res 2007; 67: 3: 1282-1290.

22. Nagahara Y., Shiina I., Nakata K. et al. Induction of mitochondria-involved apoptosis in estrogen receptor-negative cells by a novel tamoxifen derivative, ridaifen-B. Cancer Sci 2008; 99: 3: 608-614.

23. Kallio A., Zheng A., Dahllund J. et al. Role of mitochondria in tamoxifen-induced rapid death of MCF-7 breast cancer cells. Apoptosis 2005; 10: 6: 1395-1410.

24. Bursch W., Ellinger A., Kienzl H. et al. Active cell death induced by the anti-estrogens tamoxifen and ICI 164 384 in human mammary carcinoma cells (MCF-7) in culture: the role of autophagy. Carcinogenesis 1996; 17: 8: 1595-1607.

25. Bursch W., Hochegger K., Torok L. et al. Autophagic and apoptotic types of programmed cell death exhibit different fates of cytoskeletal filaments. J Cell Sci 2000; 113: 7: 1189-1198.

26. Zulehner N., Maurer M., Wesierska-Gadek J. Effect of anti-estrogen combined with roscovitine, a selective CDK inhibitor, on human breast cancer cells differing in expression of ER. J Exp Ther Oncol 2011; 9: 1: 17-25.

27. Węsierska-Gqdek J., Gritsch D., Zulehner N. et al. Roscovitine, a selective CDK inhibitor, reduces the basal and estrogen-induced phosphorylation of ER-a in human ER-positive breast cancer cells. J Cell Biochem 2011; 112: 3: 761-772.

28. Wçsierska-Gądek J., Gritsch D., Zulehner N. et al. Interference with ERa enhances the therapeutic efficacy of the selective CDK inhibitor roscovitine towards ER-positive breast cancer cells. J Cell Biochem 2011; 112: 4: 1103-1117.

29. O'Byrne K.J., Dalgleish A.G., Browning M.J. et al. The relationship between angiogenesis and the immune response in carcinogenesis and the progression of malignant disease. Eur J Cancer 2000; 36: 2: 151-169.

30. Da Silva B.B., da Silva Junior R.G., Borges U.S. et al. Quantification of angiogenesis induced in rabbit cornea by breast carcinoma of women treated with tamoxifen. J Surg Oncol 2005; 90: 2: 77-80.

31. Blackwell K.L., Haroon Z.A., Shan S. et al. Tamoxifen inhibits angio-genesis in estrogen receptor-negative animal models. Clin Cancer Res 2000; 6: 11: 4359-4364.

32. Cáceres W., González S. Angiogenesis and cancer: recent advances. P R Health Sci J 2003; 22: 2: 149-151.

33. Tong S., Chen Q., Shan S.Q. et al. Quantitative comparison of the inhibitory effects of GW5638 and tamoxifen on angiogenesis in the cornea pocket assay. Angiogenesis 2006; 9: 2: 53-58.

34. Gagliardi A.R., Hennig B., Collins D.C. Antiestrogens inhibit endothelial cell growth stimulated by angiogenic growth factors. Anticancer Res 1996; 16: 3A: 1101-1106.

35. Butta A., MacLennan K., Flanders K.C. et al. Induction of transforming growth factor beta 1 in human breast cancer in vivo following tamoxifen treatment. Cancer Res 1992; 52: 15: 4261-4264.

36. Garvin S., Dabrosin C. Tamoxifen inhibits secretion of vascular endothelial growth factor in breast cancer in vivo. Cancer Res 2003; 63: 8742-8748.

37. Bilir A., Altinoz M.A., Erkan M. et al. Autophagy and nuclear changes in FM3A breast tumor cells after epirubicin, medroxyprogesterone and tamoxifen treatment in vitro. Pathobiology 2001; 69: 3: 120-126.

38. Scarlatti F., Bauvy C., Ventruti A. et al. Ceramide-mediated macroautophagy involves inhibition of protein kinase B and up-regulation of beclin 1. J Biol Chem 2004; 279: 18: 18384-18391.

39. Amaravadi R.K., Yu D., Lum J.J. et al. Autophagy inhibition enhances therapy-induced apoptosis in a Myc-induced model of lymphoma. J Clin Invest 2007; 117: 2: 326-336.

40. Nagarkatti N., Davis B.A. Tamoxifen induces apoptosis in Fas+ tumor cells by upregulating the expression of Fas ligand. Cancer Chemother Pharmacol 2003; 51: 4: 284-290.

41. Lagadec C., Adriaenssens E., Toillon R.A. et al. Tamoxifen and TRAIL synergistically induce apoptosis in breast cancer cells. Oncogene 2008; 27: 10: 1472-1477.

42. Aberg U.W., Saarinen N., Abrahamsson A. et al. Tamoxifen and flaxseed alter angiogenesis regulators in normal human breast tissue in vivo. PLoS One 2011; 6: 9: e25720.

43. McNamara D.A., Harmey J., Wang J.H. et al. Tamoxifen inhibits endothelial cell proliferation and attenuates VEGF-mediated angiogenesis and migration in vivo. Eur J Surg Oncol 2001; 27: 8: 714-718.

44. Lindahl G., Saarinen N., Abrahamsson A., Dabrosin C. Tamoxifen, flaxseed, and the lignan enterolactone increase stroma- and cancer cell-derived IL-1Ra and decrease tumor angiogenesis in estrogen-dependent breast cancer. Cancer Res 2011; 71: 1: 51-60.

45. Hotta T., Tanimura H., Yamaue H. Tamoxifen circumvents the multidrug resistance in fresh human gastrointestinal cancer cells. J Surg Res 1996; 66: 1: 31-35.

46. Shen L.Z., Hua Y.B., Yu X.M. Tamoxifen can reverse multidrug resistance of colorectal carcinoma in vivo. World J Gastroenterol 2005; 11: 7: 1060-1064.

47. Safa A.R., Roberts S., Agresti M., Fine R.L. Tamoxifen aziridine, a novel affinity probe for P-glycoprotein in multidrug resistant cells. Biochem Biophys Res Commun 1994; 202: 1: 606-612.

48. Rao U.S., Fine R.L., Scarborough G.A. Antiestrogens and steroid hormones: substrates of the human P-glycoprotein. Biochem Pharmacol 1994; 48: 2: 287-292.

49. Liu Z.H., Ma Y.L., He Y.P. et al. Tamoxifen reverses the multi-drug-resistance of an established human cholangiocarcinoma cell line in combined chemotherapeutics. Mol Biol Rep 2011; 38: 3: 1769-1775.

50. Bogush E.A., Ravcheeva A.B., Bogush T.A. et al. A new marker of tamoxifen resistance of estrogen receptor-positive breast cancer. Dokl Biochem Biophys 2007; 413: 83-87.

51. Bogush T.A., Dudko E.A., Bogush E.A. et al. MRP as a new predictive marker of tamoxifen efficiency in treatment of estrogen receptor-positive breast cancer. Dokl Biochem Biophys 2010; 430: 36-40.

52. Bogush T.A., Dudko E.A., Beme A.A. et al. Estrogen receptor expression in tumors different from breast cancer. Antibiot Khimioter 2009; 54: 7-8: 41-49.

53. Bogush T.A., Dudko E.A., Beme A.A. et al. Estrogen receptors, antiestrogens, and non-small cell lung cancer. Biochemistry (Mosc) 2010; 75: 12: 1421-1427.