Fas-mediated killing of primary prostate cancer cells is increased by mitoxantrone and docetaxel

Abstract

Therapies for prostate cancer based on Fas (CD95) modulation have been under active development at the preclinical stage using immortalized cell lines. To address clinical applicability, the potential of 11 cultures of primary prostate cancer cells to be killed by Fasmediated apoptosis was investigated. In addition, the effect of the chemotherapeutic agents mitoxantrone and docetaxel on this killing was determined. Apoptosis was induced in patient-derived, primary prostate cancer cells using effector cells engineered by recombinant lentivirus infection to express Fas ligand (FasL) and measured by 51 Cr release assays. All cultured prostate cells were found to undergo Fas-mediated killing; cytotoxicity ranged from 12% to 87% after 6 h. These cells were significantly more sensitive to FasL-mediated killing than PC-3 cells. The basal expression of Fas or the expression of five inhibitors of apoptosis (c-FLIP, survivin, cellular inhibitors of apoptosis protein 1 and 2, and bcl-2) was not found to correlate with susceptibility to Fasmediated killing. Both mitoxantrone and docetaxel were able to induce Fas receptor expression on primary prostate cancer cells, which translated into a 1.5-to 3-fold enhancement of apoptosis mediated by FasL. Whereas mitoxantrone increased the Fas-induced apoptotic response of all cultured prostate cells tested, docetaxel pretreatment was found to preferentially enhance the killing of bcl-2-expressing cells. These findings show that cultured primary prostate cancer cells are sensitive to Fas-mediated apoptosis. Furthermore, the incidence of apoptosis was found to be improved by combining Fas-mediated therapy with standard chemotherapeutic agents. These findings may have significant implications for prostate cancer therapy.

Selective estrogen receptor modulators regulate stromal proliferation in human benign prostatic hyperplasia by multiple beneficial mechanisms—action of two new agents

“…Hence BP utilizes multiple beneficial mechanisms for action in prostatic stromal cells as compared with other SERMs. Alternatively, this also indicates the potential of BP as a chemoprotectant for prostatic cancer since ER-ß, TNF-α, TGFß1 and Fas/FasL mediated actions have been shown to be important in regulation of prostatic carcinoma [49,50]. However this aspect needs further validation.…”

Retrovirally transduced murine T lymphocytes expressing FasL mediate effective killing of prostate cancer cells

“…We have previously shown that K562-ncFasL cells induce cytolysis in primary human prostate cancer epithelial cells 12. However, when FasL-expressing T cells were substituted with ncFasL-expressing K562 cells in similar killing assays, RM-1 and LNCaP cells failed to undergo any measurable cytotoxicity (Figure 6a).…”

“…We have previously shown that treatment of primary prostate cancer cells with mitoxantrone or docetaxel not only increases Fas expression levels on these cells but improves Fas-mediated killing of drug-treated cells by up to 3-fold 12. As basal levels of Fas were low on RM-1 cells compared with murine TRAMP-C1, human LNCaP, and PC-3 cells (Figure 7a), we sought to increase the expression of this receptor.…”

“…Delivery of FasL cDNA by a prostate-restricted replicative adenovirus inhibited prostate tumor growth in mice 11. Furthermore, we have recently demonstrated that primary human prostate cancer cell lines are sensitive to killing by FasL-expressing K562 cells 12. Although systemic distribution of soluble FasL (sFasL) proteins or anti-Fas antibodies are lethal in vivo ,13 cell surface-expressed FasL does not seem to share this potency.…”

Mitoxantrone-Induced Suicidal Erythrocyte Death

“…The antineoplastic effects result from triggering of tumor cell apoptosis [11,12,13,14,15,16,17], the efficacy of mitoxantrone in multiple sclerosis has been attributed to apoptosis of lymphocytes and dendritic cells [18]. Furthermore, mitoxantrone may induce cell senescence [19].…”