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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Strategy for reversing resistance to a single anticancer agent in human prostate and pancreatic carcinomas
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Strategy for reversing resistance to a single anticancer agent in human prostate and pancreatic carcinomas

机译：逆转人前列腺癌和胰腺癌对单一抗癌药耐药性的策略

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Effective therapies for most solid cancers, especially those that have progressed to metastasis, remain elusive because of inherent and acquired resistance of tumor cells to conventional treatments. Additionally, the effective therapeutic window for many protocols can be very narrow, frequently resulting in toxicity. The present study explores an anticancer strategy that effectively eliminates resistant cancer cells without exerting deleterious effects on normal cells. This approach employs melanoma differentiation-induced gene-7/interleukin-24 (mda-7/IL-24), a cancer-specific, apoptosis-inducing cytokine, in combination with nontoxic doses of a chemical compound from the endoperoxide class that decomposes in water generating singlet oxygen. This combinatorial regimen specifically induced in vitro apoptosis in prostate carcinoma cells, with innate resistance to chemotherapy or engineered resistance to mda-7/IL-24, as well as pancreatic carcinoma cells inherently resistant to any treatment modality, including mda-7/IL-24. Apoptosis induction correlated with increased cellular reactive oxygen species production and was prevented by general antioxidants, such as N-acetyl-L-cysteine or Tiron. Induction of apoptosis in combination-treated cancer cells correlated with a reduction in the antiapoptotic protein BCL-x_L. In contrast, both normal prostate and pancreatic epithelial cells were unaffected by the single or combination treatment. These provocative findings suggest that this combinatorial strategy might provide a platform. for developing effective treatments for therapy-resistant cancers.
机译：由于肿瘤细胞对常规治疗的固有的和获得性的抵抗力，因此对于大多数实体癌，特别是已经转移的实体癌，有效的治疗方法仍然难以捉摸。另外，许多方案的有效治疗窗口可能非常狭窄，经常导致毒性。本研究探索了一种抗癌策略，该策略可有效消除耐药性癌细胞，而不会对正常细胞产生有害影响。该方法采用黑素瘤分化诱导基因7 /白细胞介素24（mda-7 / IL-24）（一种癌症特异性，诱导细胞凋亡的细胞因子），结合无毒剂量的内过氧化物类化合物分解为水产生单线态氧。此组合方案可特异性诱导前列腺癌细胞的体外凋亡，对化疗具有先天性抵抗力或对mda-7 / IL-24的工程性抵抗力，以及对任何治疗方式（包括mda-7 / IL- 24凋亡诱导与细胞活性氧产生的增加有关，并被一般的抗氧化剂如N-乙酰基-L-半胱氨酸或Tiron所阻止。联合治疗的癌细胞凋亡的诱导与抗凋亡蛋白BCL-x_L的减少有关。相反，正常的前列腺和胰腺上皮细胞都不受单一或联合治疗的影响。这些具有启发性的发现表明，这种组合策略可能会提供一个平台。开发有效的抗治疗性癌症治疗方法。

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