Tamoxifen magnifies therapeutic impact of ceramide in human colorectal cancer cells independent of p53.
Tamoxifen magnifies therapeutic impact of ceramide in human colorectal cancer cells independent of p53.
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DOI：
10.1016/j.bcp.2013.01.015
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发表时间：
2013-04-15
影响因子：
5.8
通讯作者：
Cabot, Myles C.
中科院分区：
文献类型：
--
作者：
Morad, Samy A. F.;Madigan, James P.;Levin, Jonathan C.;Abdelmageed, Noha;Karimi, Ramin;Rosenberg, Daniel W.;Kester, Mark;Shanmugavelandy, Sriram S.;Cabot, Myles C.
晚期结直肠癌（CRC）患者预后不良，需要寻找新的治疗策略。神经酰胺，由于其在协调癌细胞死亡级联反应中的作用，是一种通用的替代品。神经酰胺可以通过暴露于化学疗法或电离辐射产生，或者它可以以短链类似物（C6-神经酰胺）的形式施用。由于细胞内P-糖蛋白（P-gp）在催化神经酰胺转化为高级鞘脂中起作用，我们假设给予P-gp拮抗剂和C6-神经酰胺会放大细胞死亡级联反应。使用人CRC细胞系HCT-15、HT-29和LoVo。添加他莫昔芬、VX-710、维拉帕米或环孢菌素A（P-gp拮抗剂）可增强所有细胞系中C6-神经酰胺的细胞毒性。在LoVo细胞中使用C6-神经酰胺和他莫昔芬进行的深入研究显示，该方案诱导PARP裂解、半胱天冬酶依赖性凋亡、线粒体膜透化（MMP）以及G1和G2期细胞周期停滞。在分子水平上，该方案，但不是单一的代理商，诱导肿瘤抑制蛋白p53的时间依赖性上调，然而，引入p53抑制剂延缓既不MMP也不凋亡。C6-神经酰胺和他莫昔芬的纳米脂质体制剂也是有效的，产生协同细胞杀伤。我们的结论是，他莫昔芬是一个有利的佐剂，提高C6-神经酰胺细胞毒性CRC，并表现出独特的综合效果。P-gp在CRC中的高表达频率为补充基于神经酰胺的治疗提供了一个外源性靶点，这是一种有望治疗耐药疾病的策略。
Poor prognosis in patients with later stage colorectal cancer (CRC) necessitates the search for new treatment strategies. Ceramide, because of its role in orchestrating death cascades in cancer cells, is a versatile alternative. Ceramide can be generated by exposure to chemotherapy or ionizing radiation, or it can be administered in the form of short-chain analogs (C6-ceramide). Because intracellular P-glycoprotein (P-gp) plays a role in catalyzing the conversion of ceramide to higher sphingolipids, we hypothesized that administration of P-gp antagonists with C6-ceramide would magnify cell death cascades. Human CRC cell lines were employed, HCT-15, HT-29, and LoVo. The addition of either tamoxifen, VX-710, verapamil, or cyclosporin A, antagonists of P-gp, enhanced C6-ceramide cytotoxicity in all cell lines. In depth studies with C6-ceramide and tamoxifen in LoVo cells showed the regimen induced PARP cleavage, caspase-dependent apoptosis, mitochondrial membrane permeabilization (MMP), and cell cycle arrest at G1 and G2. At the molecular level, the regimen, but not single agents, induced time-dependent upregulation of tumor suppressor protein p53; however, introduction of a p53 inhibitor staved neither MMP nor apoptosis. Nanoliposomal formulations of C6-ceramide and tamoxifen were also effective, yielding synergistic cell kill. We conclude that tamoxifen is a favorable adjuvant for enhancing C6-ceramide cytotoxicity in CRC, and demonstrates uniquely integrated effects. The high frequency of expression of P-gp in CRC presents an adventitious target for complementing ceramide-based therapies, a strategy that could hold promise for treatment of resistant disease.
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影响因子：
5.3
作者：
Habold C;Poehlmann A;Bajbouj K;Hartig R;Korkmaz KS;Roessner A;Schneider-Stock R
通讯作者：
Schneider-Stock R
影响因子：
10.5
作者：
Naik, P;Karrim, J;Hanahan, D
通讯作者：
Hanahan, D
影响因子：
20.3
作者：
Liu, Xin;Ryland, Lindsay;Loughran, Thomas P., Jr.
通讯作者：
Loughran, Thomas P., Jr.
影响因子：
4.8
作者：
Lavie, Y;Cao, HT;Cabot, MC
通讯作者：
Cabot, MC
影响因子：
10.3
作者：
Maurer, BJ;Melton, L;Reynolds, CP
通讯作者：
Reynolds, CP