Abstract 902: The antiandrogen bicalutamide induces senescence in LNCaP cells and quiescence in Myc CaP cells

The survival benefits in prostate cancer (PCa) conferred by androgen deprivation therapies (ADT) and antiandrogens are often blunted by the development of castration resistant disease (CRPC). There is increasing evidence that the primary cellular response to ADT is senescence rather than apoptosis, and this may influence progression to CRPC. However, the majority of in vitro studies employ the charcoal stripped serum model, and very few studies use antiandrogens, despite the fact that antiandrogens are currently one of the primary modes of therapy for prostate cancer. In an effort to enhance our understanding of antiandrogen effects in PCa, we evaluated the cellular response to the clinically relevant antiandrogen, bicalutamide, in the human LNCaP and murine Myc-CaP cell lines. Acute treatment (48 hours) with bicalutamide resulted in a growth arrest followed by proliferative recovery in both cell lines. However, while the growth arrest was prolonged (lasting at least 6 days) in the LnCaP cells, growth arrest was exceedingly brief (lasting approximately 24 hours) in the Myc-CaP cells. Consistent with these observations, we were able to detect increased beta galactosidase staining (a hallmark of senescence) in the LnCaP treated cells but not the Myc-CaP treated cells. Despite the fact that profound morphological changes were evident in the Myc-Cap cells, including an enlarged and elongated cell body, the highly transient nature of the growth arrest suggests that the Myc-Cap cells undergo quiescence rather than senescence. The absence of senescence induction in the Myc-CaP cells may be a consequence of the androgen receptor copy number gain. However, androgen duplication is highly uncommon in human prostate cancers prior to development of CRPC. Thus, it is likely that antiandrogens can induce senescence in treatment-naïve patients, as seen in the LNCaP cell line. The ability of bicalutamide to induce senescence, albeit perhaps conditionally, suggests that some prostate cancers treated with ADT and/or antiandrogens may be susceptible to drugs that target senescent cells (senolytics). We therefore propose that elimination of senescent cells prior to recovery could attenuate or prevent the development of CRPC. Citation Format: Valerie J. Carpenter, Tareq Saleh, David A. Gewirtz. The antiandrogen bicalutamide induces senescence in LNCaP cells and quiescence in Myc CaP cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting