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首页> 外文期刊>Growth Factors >Improvement of cytotoxic effects induced by mitoxantrone on hormone-refractory metastatic prostate cancer cells by co-targeting epidermal growth factor receptor and hedgehog signaling cascades.
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Improvement of cytotoxic effects induced by mitoxantrone on hormone-refractory metastatic prostate cancer cells by co-targeting epidermal growth factor receptor and hedgehog signaling cascades.

机译：通过共同靶向表皮生长因子受体和刺猬信号级联，改善米托蒽醌对激素难治性转移性前列腺癌细胞的细胞毒性作用。

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摘要

The results of the present study revealed for the first time the possibility to use a combination of mitoxantrone with gefitinib and cyclopamine for inhibiting the growth of epidermal growth factor (EGF), sonic hedgehog- (SHHNp), and serum-stimulated androgen-sensitive LNCaP-C33 and androgen-independent (AI) LNCaP-C81, DU145 and PC3 prostate cancer (PC) cells. The supra-additive anti-proliferative effects of drugs were mediated via a blockade of the PC3 cells in the G(1) and G(2)M phases of the cell cycle. Importantly, the combination of mitoxantrone plus gefitinib and/or cyclopamine also caused a higher rate of apoptotic death of PC cells including enriched fraction of CD44(high) PC3 cell subpopulation as compared to the individual agents or bi-combination of drugs. The cytotoxic effects induced by mitoxantrone, gefitinib and cyclopamine on PC3 cells appear to be at least partly mediated through the depolarization of the mitochondrial membrane, release of cytochrome c into the cytosol, hydrogen peroxide production and activation of caspase cascades. These findings indicate that the simultaneous blockade of EGF-EGFR and sonic hedgehog tumorigenic signaling cascades may represent a promising strategy for improving the efficacy of current mitoxantrone-based therapies against incurable AI and metastatic PCs in the clinics.
机译：本研究的结果首次揭示了米托蒽醌与吉非替尼和环巴胺的组合可用于抑制表皮生长因子（EGF），声波刺猬（SHHNp）和血清刺激的雄激素敏感性LNCaP的可能性-C33和非雄激素依赖性（AI）LNCaP-C81，DU145和PC3前列腺癌（PC）细胞。药物的超加性抗增殖作用是通过在细胞周期的G（1）和G（2）M期阻断PC3细胞来介导的。重要的是，与单独的药物或药物的双重组合相比，米托蒽醌加吉非替尼和/或环巴胺的组合还引起较高的PC细胞凋亡死亡率，包括CD44（高）PC3细胞亚群的富集部分。米托蒽醌，吉非替尼和环巴胺对PC3细胞诱导的细胞毒性作用似乎至少部分是通过线粒体膜的去极化，细胞色素c释放到细胞质溶胶，过氧化氢的产生以及胱天蛋白酶级联反应的激活来介导的。这些发现表明，同时阻断EGF-EGFR和声波刺猬的致瘤信号传导级联可能代表一种有希望的策略，可提高临床上基于米托蒽醌的治疗方法对不可治愈的AI和转移性PC的疗效。

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