Login to Access Video or Poster Abstract: MP57-02
Sources of Funding: Studies supported in part by VA Merit Award-01BX001258 (HK), NIH/NCI R01CA161880 (HK), Carroll W. Feist endowed Chair Funds (Koul H), and FWCC (KK)._x000D_

Introduction

Prostate cancer (PCa) is the second leading cause of cancer deaths in men. AR signaling is known to play a critical role in androgen responsive prostate cancer cells. Androgen deprivation therapy (ADT) is a standard of care for patients when prostate cancer has spread beyond the prostate. Almost all the prostate cancer (PCa) deaths result from castration resistant prostate cancer (CRPC). With the development of newer anti-androgen Enzalutamide (ENZ) there has been a marked improvement in CRPC. However, almost all patients develop resistance to ENZ in part due to expression of ARv7. Thus, to date, no acceptable treatment options are available for ENZ resistant CRPC. In the present study we evaluated the effects of TET, a derivative of bis-benzyly isoquinoline, Tetrandrine on two enzalutamide resistant prostate cancer cell lines on sensitizing these cells to Enzalutamide. We also evaluated the effects of TET on AR and ARv7 levels._x000D_

Methods

Enz resistant Prostate cancer cell lines (22rv1 and LNCaP-abl) were used in the present study. Cells were grown in supplemented media and maintained at 370C in a 5%CO2 incubator (as described elsewhere). Where indicated cells were treated with Enzalutamide or TET alone or in combination. Cell viability was measured by crystal violet and MTT assays. Protein levels were measured by Western Blot assays. mRNA expression measured in RTPCR assays._x000D_

Results

Treatment with Enz had only a marginal effect on growth and viability of 22rv1 cells. TET inhibited growth and proliferation of enzalutamide resistant prostate cancer cells in both dose and time dependent manner with an IC50 in the range of 5-10uM at 72 hr. However TET treatment did not result in death of RWPE cells, a line of normal prostate cells. Moreover, combination of TET and Enz was more effective than either treatment alone. Treatment with TET resulted in decreased levels of full length AR as well as ARv7 within 24-48h. We also observed that TET treatment was associated with decreased cyclin D1 and increased CDK inhibitors p21 and p27. Over all Tet alone and in combination with Enz promoted cell growth arrest and cell death in ENZ resistant CRPC cells and sensitized these cells to Enz._x000D_

Conclusions

This study shows that TET sensitizes CRPC cells to Enz in part by decreasing protein levels of AR and ARv7.

Funding

Studies supported in part by VA Merit Award-01BX001258 (HK), NIH/NCI R01CA161880 (HK), Carroll W. Feist endowed Chair Funds (Koul H), and FWCC (KK)._x000D_