研究人员鉴定出一系列能保护细胞免受常用化疗药物阿霉素(doxorubicin)伤害的基因。
美国乔治亚医学院癌症中心的研
究人员Hernan Flores-Rozas博士指出,他们发现了一系列对细胞在接触到阿霉素时得以存活至关重要的基因。当你开始失活这些基因时,细胞变得非常敏感并且不再生长。因此,研究人员现在已经知道通过失活哪些基因能够使其对这种药物变得非常敏感。
阿霉素广泛用于治疗从乳腺癌到前列腺和卵巢癌的一系列实体肿瘤。一个稍加修饰的版本——柔毛霉素(doxorubicin)是一种强大的抗白血病和淋巴瘤药物,常常用于治疗儿童患者。
但不幸的是,在癌症治疗结束时,许多使用这种药物的患者又会出现心脏问题。武汉大学在该研究中心的交换博士生夏玲(女,Ling Xia,音译)解释说,心肌细胞会发生细胞凋亡。而这种凋亡过程的结果就是出现心肌症,即心脏不能再向着身体各个方向泵血。这种损伤甚至在治疗后数年才发生,目前还没有办法来预防或治疗,除了进行心脏移植。
他们的研究的长期目标是通过找到关闭癌细胞中这些基因的方法来预防并改善癌症治疗效果。这项研究的结果发表在12月1日的Cancer Research上,文章的第一作者是夏玲。
夏玲博士与Hernan Flores-Rozas在实验室
他们在相对简单的酵母细胞中进行了研究。酵母只有6000个基因,是人类细胞研究的好模型,因为它们包含了相同的基础细胞功能如复制、DNA修复、信号途径和细胞死亡。
他们发现71个基因能为细胞提供针对阿霉素的不同程度的保护作用。细胞没有一个特殊的机制来保护阿霉素的毒害,一些基因的保护作用强于另外一些基因。诞生在缺少一些基因时,细胞会因接触这种药物而发生死亡。
研究人员指出,这些新确定的保护性基因可能在细胞接触到化疗药物之前已经发生了一定程度的表达,然后在接触这种药物是进一步增加表达。MCG的研究人员推测,这些基因可能还可对其他胁迫如病毒感染等提供保护。目前,他们正在分析这些基因的功能和在癌症、心脏细胞中的表达情况。
原始出处:
Cancer Research 67, 11411-11418, December 1, 2007. doi: 10.1158/0008-5472.CAN-07-2399
Experimental Therapeutics, Molecular Targets, and Chemical Biology
Identification of Genes Required for Protection from Doxorubicin by a Genome-Wide Screen in Saccharomyces cerevisiae
Ling Xia1, Lahcen Jaafar1, Anil Cashikar2 and Hernan Flores-Rozas1,3
1 Institute of Molecular Medicine and Genetics, 2 Center for Molecular Chaperone/Radiobiology and Cancer Virology Group, and 3 Department of Medicine, Medical College of Georgia, Augusta, Georgia
Requests for reprints: Hernan Flores-Rozas, Medical College of Georgia, 1120 15th Street, CB-2803, Augusta, GA 30912. Phone: 706-721-1371; Fax: 706-721-8752; E-mail: hfloresrozas@mail.mcg.edu .
Anthracyclines are chemotherapeutic agents commonly used to treat a broad range of malignancies. Although effective, these drugs present serious complications, most notably cardiotoxicity. To determine the mechanisms that mediate cytoprotection from doxorubicin, we have screened the collection of Saccharomyces cerevisiae haploid gene deletion mutants. We have identified 71 deletion strains that display varying degrees of hypersensitivity to doxorubicin at a concentration that does not significantly reduce the viability of wild-type cells. Complementation of the doxorubicin-sensitive phenotype of the deletion strains with the wild-type genes proves that the sensitivity of the strain to doxorubicin is due to the gene deletion. The genes that mediate cytoprotection from doxorubicin belong to multiple pathways including DNA repair, RNA metabolism, chromatin remodeling, amino acid metabolism, and heat shock response. In addition, proteins with mitochondrial, osmosensing, vacuolar, and ribosomal functions are also required for protection from doxorubicin. We tested the sensitivity of the deletion strains to other cytotoxic agents, which resulted in different drug-specific sensitive groups. Most of the identified genes have mammalian homologues that participate in conserved pathways. Our data may prove useful to develop strategies aimed at sensitizing tumor cells to doxorubicin as well as protecting cardiac cells from its cytotoxic effects. [Cancer Res 2007;67(23):11411–8]