Thamilselvan Vijayalakshmi, Menon Mani, Thamilselvan Sivagnanam
Vattikuti Urology Institute, Henry Ford Health System, Detroit, MI.
Int J Cancer. 2016 Oct 1;139(7):1632-47. doi: 10.1002/ijc.30189. Epub 2016 Jun 10.
Despite established androgen receptor (AR) antagonists, AR/AR-variants signaling remain a major obstacle for the successful treatment of castration resistant prostate cancer (CRPC). In addition, CRPC cells adapt to survive via AR-independent pathways to escape next generation therapies. Therefore, there is an urgent need for drugs that can target these signaling pathways in CRPC. In this study, we sought to determine whether carmustine and selenite in combination could induce apoptosis and inhibit growth of CRPC in-vitro and in-vivo. CRPC (22Rv1, VCaP, and PC-3) cell lines in culture and xenograft mouse were used. Combination of carmustine and selenite treatment significantly increased reactive oxygen species, apoptosis and growth inhibition in CRPC cells with down regulation of anti-apoptotic (Bcl-2 and Mcl-1) and proliferative proteins (c-Myc and cyclin-D1). This effect was associated with complete reduction of AR/AR-variants, AR-V7, PSA and significant induction of p27Kip1. Combination treatment substantially abolished phospho-Akt, phospho-GSK-3β, and anchorage-independent growth in AR-positive and AR-negative cells. Consistent with in-vitro results, combination treatment effectively induced apoptosis and completely inhibited xenograft tumor growth and markedly reduced AR/AR-variants, AR-V7, PSA, and Bcl-2 in xenograft tumors without causing genotoxicity in host mice. Individual agent treatment showed only partial effect. The combination treatment showed a significant synergistic effect. The present study is the first to demonstrate that the combination of carmustine and selenite treatment completely suppressed CRPC tumor growth by reducing AR/AR-variants and Akt signaling. Our findings suggest that the combination of carmustine and selenite could constitute a promising next-generation therapy for successful treatment of patients with CRPC.
尽管已有雄激素受体（AR）拮抗剂，但AR/AR变体信号传导仍是去势抵抗性前列腺癌（CRPC）成功治疗的主要障碍。此外，CRPC细胞通过不依赖AR的途径适应生存，以逃避下一代疗法。因此，迫切需要能够靶向CRPC中这些信号通路的药物。在本研究中，我们试图确定卡莫司汀和亚硒酸盐联合使用是否能在体外和体内诱导CRPC细胞凋亡并抑制其生长。使用了培养的CRPC（22Rv1、VCaP和PC-3）细胞系和异种移植小鼠。卡莫司汀和亚硒酸盐联合处理显著增加了CRPC细胞中的活性氧、凋亡和生长抑制，同时下调了抗凋亡蛋白（Bcl-2和Mcl-1）和增殖蛋白（c-Myc和细胞周期蛋白D1）。这种效应与AR/AR变体、AR-V7、前列腺特异性抗原（PSA）的完全降低以及p27Kip1的显著诱导有关。联合处理基本消除了AR阳性和AR阴性细胞中的磷酸化Akt、磷酸化糖原合成酶激酶-3β（phospho-GSK-3β）以及非锚定依赖性生长。与体外结果一致，联合处理有效地诱导了凋亡，完全抑制了异种移植肿瘤的生长，并显著降低了异种移植肿瘤中的AR/AR变体、AR-V7、PSA和Bcl-2，且未对宿主小鼠造成遗传毒性。单独药物处理仅显示出部分效果。联合处理显示出显著的协同效应。本研究首次证明，卡莫司汀和亚硒酸盐联合处理通过降低AR/AR变体和Akt信号传导完全抑制了CRPC肿瘤生长。我们的研究结果表明，卡莫司汀和亚硒酸盐联合使用可能构成一种有前景的下一代疗法，用于成功治疗CRPC患者。
