Resistance to cisplatin and paclitaxel does not affect the sensitivity of human ovarian cancer cells to antiprogestin-induced cytotoxicity.
Resistance to cisplatin and paclitaxel does not affect the sensitivity of human ovarian cancer cells to antiprogestin-induced cytotoxicity.
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DOI：
10.1186/1757-2215-7-45
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发表时间：
2014
影响因子：
4
通讯作者：
Telleria CM
中科院分区：
文献类型：
--
作者：
Gamarra-Luques CD;Hapon MB;Goyeneche AA;Telleria CM
抗卵巢癌蛋白化合物已被证明可有效阻断不同遗传背景的卵巢癌细胞的生长。在此，我们研究了一系列抗孕激素的抗卵巢癌作用，这些抗孕激素与最具特征的抗孕激素米非司酮的化学骨架共享，但在类固醇环的C-17位具有独特的修饰。我们评估了米非司酮样抗孕激素对卵巢癌细胞生长的影响，卵巢癌细胞对标准联合治疗顺铂-紫杉醇敏感，或在临床相关浓度和暴露时间下使用药物进行6个周期的脉冲选择后产生双重耐药。IGF-I和SKOV-3细胞用20 μM顺铂脉冲1小时，然后用100 nM紫杉醇脉冲3小时，每周一次，持续6周。化疗后没有死亡并重新填充培养物的细胞被称为铂-紫杉烷-逃逸细胞（PTES）。将亲本细胞与它们的PTES衍生物在它们对进一步铂-紫杉烷处理的响应中进行比较。此外，卵巢癌细胞和它们的PTES兄弟姐妹都暴露于剂量递增的各种抗卵巢癌蛋白衍生物。我们使用微毛细管细胞术评估细胞生长、活力和亚G1 DNA含量。使用细胞周期蛋白依赖性激酶抑制剂p21 cip 1和p27 kip 1以及下游半胱天冬酶-3底物PARP的裂解来评估细胞命运（作为处理的结果）是否限于细胞停滞或进展至致死。经过顺铂-紫杉醇的六个脉冲选择周期的细胞产生了对进一步化疗的敏感性降低约2-7倍的同胞衍生物。然而，不管细胞对顺铂-紫杉醇组合的敏感性如何，它们对抗孕激素显示出相似的敏感性，抗孕激素以剂量相关的方式阻断它们的生长，较低浓度导致细胞停滞，较高浓度导致致死。携带类似于米非司酮的骨架的抗孕激素对卵巢癌细胞具有细胞毒性，其方式不依赖于细胞对标准卵巢癌化疗药物顺铂和紫杉醇的敏感性。因此，抗卵巢癌蛋白疗法可用于治疗对铂和紫杉烷类均显示耐药性的卵巢癌细胞。
Antiprogestin compounds have been shown to be effective in blocking the growth of ovarian cancer cells of different genetic backgrounds. Herein we studied the anti-ovarian cancer effect of a series of antiprogestins sharing the chemical backbone of the most characterized antiprogestin, mifepristone, but with unique modifications in position C-17 of the steroid ring. We assessed the effect of mifepristone-like antiprogestins on the growth of ovarian cancer cells sensitive to the standard combination therapy cisplatin-paclitaxel or made double-resistant upon six cycles of pulse-selection with the drugs used at clinically relevant concentrations and exposure times. IGROV-1 and SKOV-3 cells were pulsed with 20 μM cisplatin for 1 h followed by 100 nM paclitaxel for 3 h once a week for six weeks. The cells that did not die and repopulate the culture after the chemotherapies were termed Platinum-Taxane-EScape cells (PTES). Parental cells were compared against their PTES derivatives in their responses to further platinum-taxane treatments. Moreover, both ovarian cancer cells and their PTES siblings were exposed to escalating doses of the various antiprogestin derivatives. We assessed cell growth, viability and sub-G1 DNA content using microcapillary cytometry. Cyclin-dependent kinase inhibitors p21cip1 and p27kip1 and cleavage of downstream caspase-3 substrate PARP were used to assess whether cell fate, as a consequence of treatment, was limited to cytostasis or progressed to lethality. Cells subjected to six pulse-selection cycles of cisplatin-paclitaxel gave rise to sibling derivatives that displayed ~2-7 fold reduction in their sensitivities to further chemotherapy. However, regardless of the sensitivity the cells developed to the combination cisplatin-paclitaxel, they displayed similar sensitivity to the antiprogestins, which blocked their growth in a dose-related manner, with lower concentrations causing cytostasis, and higher concentrations causing lethality. Antiprogestins carrying a backbone similar to mifepristone are cytotoxic to ovarian cancer cells in a manner that does not depend on the sensitivity the cells have to the standard ovarian cancer chemotherapeutics, cisplatin and paclitaxel. Thus, antiprogestin therapy could be used to treat ovarian cancer cells showing resistance to both platinum and taxanes.
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DOI：
10.1038/nrclinonc.2013.5
发表时间：
2013-04
期刊：
Nature reviews. Clinical oncology
影响因子：
--
作者：
通讯作者：
--
影响因子：
8
作者：
Cooke, S. L.;Ng, C. K. Y.;Melnyk, N.;Garcia, M. J.;Hardcastle, T.;Temple, J.;Langdon, S.;Huntsman, D.;Brenton, J. D.
通讯作者：
Brenton, J. D.
DOI：
10.1038/nrc2644
发表时间：
2009-06
期刊：
Nature reviews. Cancer
影响因子：
--
作者：
通讯作者：
--
影响因子：
2.4
作者：
Kurata, T;Tamura, T;Saijo, N
通讯作者：
Saijo, N
影响因子：
5.3
作者：
Lewis-Tuffin, Laura J.;Jewell, Christine M.;Cidlowski, John A.
通讯作者：
Cidlowski, John A.