Modulation of vinblastine cytotoxicity by dilantin (phenytoin) or the protein phosphatase inhibitor okadaic acid involves the potentiation of anti-mitotic effects and induction of apoptosis in human tumour cells.
Modulation of vinblastine cytotoxicity by dilantin (phenytoin) or the protein phosphatase inhibitor okadaic acid involves the potentiation of anti-mitotic effects and induction of apoptosis in human tumour cells.
复制标题
通过苯妥英钠或蛋白磷酸酶抑制剂冈田酸调节长春花碱的细胞毒性涉及增强抗有丝分裂作用并诱导人类肿瘤细胞凋亡。
DOI：
10.1038/bjc.1996.33
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发表时间：
1996
影响因子：
8.8
通讯作者：
Ganapathi,R
中科院分区：
文献类型：
--
作者：
Kawamura,KI;Grabowski,D;Weizer,K;Bukowski,R;Ganapathi,R
细胞对长春花生物碱不敏感被认为主要是由于 P-糖蛋白 (P-gp) 的药物流出。抗癫痫苯妥英 (DPH) 不与 P-gp 结合，可以选择性增强野生型 (WT) 或多重耐药 (MDR) 细胞中的长春新碱 (VCR) 细胞毒性。我们现在证明，蛋白磷酸酶抑制剂冈田酸（OKA）可以通过选择性增强长春碱（VBL）而非紫杉醇和阿霉素在人白血病 HL-60 细胞中的细胞毒性来模拟 DPH 的作用。 DPH 和 OKA 均通过增强对有丝分裂纺锤体的损伤来增强 VBL 的抗有丝分裂作用，从而导致长时间的生长停滞。此外，与单独使用 VBL 不同，在用 VBL 加 DPH 处理的人类白血病或非小细胞肺癌细胞中，在无药物培养基中，有丝分裂纺锤体损伤的恢复受到损害，并且随后会因间期凋亡而导致细胞死亡。由于蛋白磷酸酶参与有丝分裂周期中细胞中期到后期过渡的调节，因此在 DPH 或 OKA 存在下增强的 VBL 细胞毒性可能涉及中期对有丝分裂纺锤体微管蛋白的影响，导致间期生长停滞和细胞凋亡。这些新颖的结果表明，DPH 或 OKA 可以成为研究长春花生物碱的细胞效应的有力工具，并可能用于开发新颖的治疗策略。
Cellular insensitivity to vinca alkaloids is suggested to be primarily due to drug efflux by P-glycoprotein (P-gp). The anti-epileptic phenytoin (DPH), which does not bind to P-gp, can selectively enhance vincristine (VCR) cytotoxicity in wild-type (WT) or multidrug-resistant (MDR) cells. We now demonstrate that the protein phosphatase inhibitor okadaic acid (OKA) can mimic the effect of DPH by selectively enhancing cytotoxicity of vinblastine (VBL), but not taxol and doxorubicin, in human leukaemia HL-60 cells. Both DPH and OKA potentiate the anti-mitotic effects of VBL by enhanced damage to the mitotic spindle, resulting in prolonged growth arrest. Also, unlike VBL alone, in human leukaemia or non-small-cell lung carcinoma cells treated with VBL plus DPH, recovery from damage to the mitotic spindle is compromised in drug-free medium and cell death by apoptosis in interphase ensues. Since protein phosphatases are involved with the regulation of metaphase to anaphase transit of cells during the mitotic cycle, enhanced VBL cytotoxicity in the presence of DPH or OKA may involve effects during metaphase on the mitotic spindle tubulin leading to growth arrest and apoptosis in interphase. These novel results suggest that DPH or OKA could be powerful tools to study cellular effects of vinca alkaloids and possibly for the development of novel therapeutic strategies.