PARP Inhibitor PJ34 Protects Mitochondria and Induces DNA-Damage Mediated Apoptosis in Combination With Cisplatin or Temozolomide in B16F10 Melanoma Cells
PARP Inhibitor PJ34 Protects Mitochondria and Induces DNA-Damage Mediated Apoptosis in Combination With Cisplatin or Temozolomide in B16F10 Melanoma Cells
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DOI：
10.3389/fphys.2019.00538
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发表时间：
2019-05-07
影响因子：
4
通讯作者：
Sumegi, Balazs
中科院分区：
文献类型：
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作者：
Cseh, Anna Maria;Fabian, Zsolt;Sumegi, Balazs
PARP-1抑制最近已用于各种恶性肿瘤（包括黑色素瘤）的单药和联合治疗，报告了有希望和矛盾的结果。虽然对潜在分子机制的更深入理解可能有助于改善临床模式，但PARP抑制剂的复杂细胞效应使得联合治疗中涉及的机制难以解开。在这里，我们使用了两种用于黑色素瘤治疗的细胞生长抑制剂与PARP抑制剂联合使用，以了解使用B16 F10黑色素瘤模型的细胞事件。我们发现，当与顺铂或替莫唑胺联合使用时，PJ 34对PARP-1的药理学阻断增强了两种烷化剂化合物的DNA损伤和细胞毒性作用。然而，有趣的是，这种协同作用相对缓慢地展开，并且在此之前是传统上被认为支持细胞存活的分子事件，包括线粒体膜电位和形态的稳定。我们的数据表明，PARP抑制剂PJ 34显然对线粒体结构和细胞存活具有相反的影响。虽然，最初，它刺激线粒体融合和超极化，线粒体保护的标志，它增强了烷化剂在后期的细胞毒性作用。这些研究结果可能有助于优化PARP基于通道的治疗模式。
PARP-1 inhibition has recently been employed in both mono-and combination therapies in various malignancies including melanoma with both promising and contradicting results reported. Although deeper understanding of the underlying molecular mechanisms may help improving clinical modalities, the complex cellular effects of PARP inhibitors make disentangling of the mechanisms involved in combination therapies difficult. Here, we used two cytostatic agents used in melanoma therapies in combination with PARP inhibition to have an insight into cellular events using the B16F10 melanoma model. We found that, when used in combination with cisplatin or temozolomide, pharmacologic blockade of PARP-1 by PJ34 augmented the DNA-damaging and cytotoxic effects of both alkylating compounds. Interestingly, however, this synergism unfolds relatively slowly and is preceded by molecular events that are traditionally believed to support cell survival including the stabilization of mitochondrial membrane potential and morphology. Our data indicate that the PARP inhibitor PJ34 has, apparently, opposing effects on the mitochondrial structure and cell survival. While, initially, it stimulates mitochondrial fusion and hyperpolarization, hallmarks of mitochondrial protection, it enhances the cytotoxic effects of alkylating agents at later stages. These findings may contribute to the optimization of PARP inhibitor-based antineoplastic modalities.