DNA Damage- But Not Enzalutamide-Induced Senescence in Prostate Cancer Promotes Senolytic Bcl-xL Inhibitor Sensitivity

Abstract

<jats:p>Cellular senescence is a natural tumor suppression mechanism defined by a stable proliferation arrest. In the context of cancer treatment, cancer cell therapy-induced senescence (TIS) is emerging as an omnipresent cell fate decision that can be pharmacologically targeted at the molecular level to enhance the beneficial aspects of senescence. In prostate cancer (PCa), TIS has been reported using multiple different model systems, and a more systematic analysis would be useful to identify relevant senescence manipulation molecular targets. Here we show that a spectrum of PCa senescence phenotypes can be induced by clinically relevant therapies. We found that DNA damage inducers like irradiation and poly (ADP-ribose) polymerase1 (PARP) inhibitors triggered a stable PCa-TIS independent of the p53 status. On the other hand, enzalutamide triggered a reversible senescence-like state that lacked evidence of cell death or DNA damage. Using a small senolytic drug panel, we found that senescence inducers dictated senolytic sensitivity. While Bcl-2 family anti-apoptotic inhibitor were lethal for PCa-TIS cells harboring evidence of DNA damage, they were ineffective against enzalutamide-TIS cells. Interestingly, piperlongumine, which was described as a senolytic, acted as a senomorphic to enhance enzalutamide-TIS proliferation arrest without promoting cell death. Overall, our results suggest that TIS phenotypic hallmarks need to be evaluated in a context-dependent manner because they can vary with senescence inducers, even within identical cancer cell populations. Defining this context-dependent spectrum of senescence phenotypes is key to determining subsequent molecular strategies that target senescent cancer cells.</jats:p>

Senolytics for Cancer Therapy: Is All that Glitters Really Gold?

“…By far, the most successful senolytic in preclinical cancer models has been navitoclax. Navitoclax has shown a remarkable capacity to eliminate tumor cells induced into senescence by a variety of therapies, including lung and melanoma cells treated with aurora kinase inhibitors or etoposide [142]; lung cancer cells treated with etoposide or radiation [27]; breast cancer cells treated with doxorubicin, radiation, or BET inhibitors [27,143,144]; ovarian cancer cells treated with PARP inhibitors [50]; and prostate tumor cells treated with PARP inhibitors or radiation [145]. Clearance of senescent tumor cells by navitoclax has been reported to enhance tumor regression/control and increase mouse survival [27,50,143].…”

“…Despite the clear effectiveness of navitoclax in pre-clinical studies, navitoclax's senolytic activity can be highly variable. For example, while prostate cancer LNCaP cells treated with antiandrogens enter senescence, the senescent cells are not eliminated by ABT-263 [145,147]; however, when treated with PARP inhibitors or radiation, the prostate tumor cells are, in fact, sensitive to senolytic action [145]. The authors have postulated that ABT-263 may only be effective in TIS systems associated with DNA-damage, a provocative concept that will require further studies for confirmation [145].…”

“…For example, as opposed to its success in the context of aging-related processes, D+Q failed to kill senescent liver cancer cells, and each drug alone failed to kill senescent ovarian cancer cells [50,150]. Piperlongumine, while showing modest senolytic activity in olaparib-treated ovarian cancer [50], failed to kill senescent prostate cells [145]. Fisetin failed to kill senescent ovarian cancer cells [50], and, in our hands, was also largely ineffective against senescent lung, head and neck, and prostate cancer cells (unpublished data).…”

“…The bulk of the published literature shows evidence of navitoclax's senolytic activity in models where senescence was induced in tumor cells by genotoxic chemotherapy, which raises the possibility that DNA damage might be a prerequisite for ABT-263 s senolytic action [145]. However, navitoclax has also been shown to target senescent tumor cells induced by the CDK 4/6 inhibitor palbociclib, which is not generally associated with classical DNA damage [168].…”

Therapy-induced normal tissue damage promotes breast cancer metastasis

“…Prolonged survival of senescent cells requires the avoidance of apoptotic-mediated cell death commonly by upregulated expression of anti-apoptotic BCL2 family members (de Carné Trécesson et al, 2011; Malaquin et al, 2020). BCL2 family proteins bind to and inhibit BH3-initiator proteins such as BAD, which would otherwise activate the apoptotic effector protein BAX to trigger caspase activation and mitochondrial outer membrane permeabilisation (Willis et al, 2003).…”