Instituto de Biomedicina de Sevilla, Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Avenida Manuel Siurot s/n, Seville 41013, Spain.
Breast Cancer Res Treat. 2012 Jun;133(3):917-28. doi: 10.1007/s10549-011-1864-9. Epub 2011 Nov 11.
Taxanes are being used for the treatment of breast cancer. However, cancer cells frequently develop resistance to these drugs with the subsequent recurrence of the tumor. MDA-MB-231 and T-47D breast cancer cell lines were used to assess the effect of paclitaxel treatment on apoptosis and cell cycle, the possible mechanisms of paclitaxel resistance as well as the enhancement of paclitaxel-induced apoptosis based on its combination with phenylethyl isothiocyanate (PEITC). T-47D cells undergo apoptosis in response to paclitaxel treatment. The induction of apoptosis was associated with a robust mitotic arrest and the disruption of Bcl-xL/Bak interaction. By contrary, MDA-MB-231 cells were insensitive to paclitaxel-induced apoptosis and this was associated with a high percentage of cells that slip out of paclitaxel-imposed mitotic arrest and also with the maintenance of Bcl-xL/Bak interaction. The sequential treatment of MDA-MB-231 cells with PEITC followed by paclitaxel inhibited the slippage induced by paclitaxel and increased the apoptosis induction achieved with any of the drugs alone. In breast cancer tissues, high Bcl-xL expression was correlated with a shorter time of disease-free survival in patients treated with a chemotherapeutic regimen that contains paclitaxel, in a statistically significant way. Thus, resistance to paclitaxel in MDA-MB-231 cells is related to the inability to disrupt the Bcl-xL/Bak interaction and increased slippage. In this context, the combination of a drug that induces a strong mitotic arrest, such as paclitaxel, with another that inhibits slippage, such as PEITC, translates into increased apoptotic induction.
紫杉烷类药物被用于治疗乳腺癌。然而，癌细胞常常对这些药物产生耐药性，导致肿瘤复发。我们使用 MDA-MB-231 和 T-47D 乳腺癌细胞系来评估紫杉醇治疗对细胞凋亡和细胞周期的影响、紫杉醇耐药的可能机制，以及基于紫杉醇与苯乙基异硫氰酸酯（PEITC）联合应用增强紫杉醇诱导的细胞凋亡的作用。T-47D 细胞对紫杉醇治疗发生凋亡。诱导的凋亡与强烈的有丝分裂阻滞和 Bcl-xL/Bak 相互作用的破坏有关。相比之下，MDA-MB-231 细胞对紫杉醇诱导的细胞凋亡不敏感，这与相当大比例的细胞从紫杉醇引起的有丝分裂阻滞中滑脱有关，并且与 Bcl-xL/Bak 相互作用的维持有关。用 PEITC 对 MDA-MB-231 细胞进行序贯治疗，然后用紫杉醇处理，可抑制紫杉醇诱导的滑脱，并增加任何一种药物单独诱导的细胞凋亡。在乳腺癌组织中，高 Bcl-xL 表达与接受包含紫杉醇的化疗方案治疗的患者无病生存时间较短显著相关。因此，MDA-MB-231 细胞对紫杉醇的耐药性与不能破坏 Bcl-xL/Bak 相互作用和增加滑脱有关。在这种情况下，将一种诱导强烈有丝分裂阻滞的药物（如紫杉醇）与另一种抑制滑脱的药物（如 PEITC）联合应用，可增强细胞凋亡诱导作用。
