Multifactorial mechanism for the potentiation of cisplatin (CDDP) cytotoxicity by all-trans retinoic acid (ATRA) in human ovarian carcinoma cell lines.
Multifactorial mechanism for the potentiation of cisplatin (CDDP) cytotoxicity by all-trans retinoic acid (ATRA) in human ovarian carcinoma cell lines.
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DOI：
10.1038/bjc.1997.55
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发表时间：
1997
影响因子：
8.8
通讯作者：
Jozan S
中科院分区：
文献类型：
--
作者：
Caliaro MJ;Vitaux P;Lafon C;Lochon I;Néhmé A;Valette A;Canal P;Bugat R;Jozan S
全反式视黄酸（ATRA）先前已显示可抑制某些人卵巢癌细胞系的增殖，并且这种抑制伴随着指示分化的细胞变化（Caliaro et al，1994）。在这项工作中，这些腺癌细胞与ATRA预处理，为各自的倍增时间，增强顺铂（CDDP）的细胞毒性，敏感的抗增殖作用，但不是在ATRA耐药的细胞系。使用中位效应分析在两个ATRA敏感细胞系（OVCCR 1和NIHOVCAR 3细胞）和一个ATRA不敏感细胞系（IGROV 1细胞）中评估结果。这两种药物之间的协同作用，观察到只有在细胞敏感的ATRA，无论他们的相对敏感性CDDP。这种协同作用的潜在机制进行了研究。ATRA不增加NIHOVCAR 3细胞内铂含量，不降低细胞内谷胱甘肽含量，对金属硫蛋白IIA mRNA水平无影响。此外，蛋白激酶C（PKC）的活性调制的分化剂在所有测试的细胞系，表明这种活性不直接参与这种增强。然而，ATRA抑制谷胱甘肽-S-转移酶活性与总DNA加合物形成的增加可以解释在NIHOVCAR 3细胞中观察到的CDDP细胞毒性的增强。最后，ATRA调节表皮生长因子（EGF）受体mRNA水平也可能与这种协同作用有关。
All-trans retinoic acid (ATRA) has been previously shown to inhibit the proliferation of some human ovarian carcinoma cell lines, and this inhibition was accompanied by cellular changes that were indicative of differentiation (Caliaro et al, 1994). In this work, a pretreatment of these adenocarcinoma cells with ATRA, for their respective doubling time, enhanced cisplatin (CDDP) cytotoxicity in the cell ines that were sensitive to its antiproliferative effect, but not in the ATRA-resistant ones. Results were assessed using median effect analysis in two ATRA-sensitive cell lines (OVCCR1 and NIHOVCAR3 cells) and in one ATRA-insensitive cell line (IGROV1 cells). Synergy between these two agents was observed only in cells sensitive to ATRA, regardless of their relative sensitivity to CDDP. Potential mechanisms for this synergy were investigated. ATRA did not increase the cellular platinum content, did not decrease the cellular glutathione and had no influence on the metallothionein IIA mRNA levels in NIHOVCAR3 cells. Moreover, the protein kinase C (PKC) activity was modulated by this differentiating agent in all cell lines tested, indicating that this activity was not directly involved in this potentiation. However, an ATRA inhibition of glutathione-S-transferase activity associated with an increase in the total DNA adducts formation could explain the potentiation of the CDDP cytotoxicity observed in NIHOVCAR3 cells. Finally, the ATRA modulation of the epidermal growth factor (EGF) receptor mRNA level could also be implicated in this synergy.