Antibiotics that target mitochondria effectively eradicate cancer stem cells, across multiple tumor types: treating cancer like an infectious disease.
Antibiotics that target mitochondria effectively eradicate cancer stem cells, across multiple tumor types: treating cancer like an infectious disease.
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DOI：
10.18632/oncotarget.3174
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发表时间：
2015-03-10
期刊：
影响因子：
--
通讯作者：
Lisanti MP
中科院分区：
文献类型：
--
作者：
Lamb R;Ozsvari B;Lisanti CL;Tanowitz HB;Howell A;Martinez-Outschoorn UE;Sotgia F;Lisanti MP
在这里，我们提出了一种治疗早期癌性病变和晚期转移性疾病的新策略，通过选择性靶向癌症干细胞（CSC），又名，肿瘤起始细胞（TIC）。我们在多种肿瘤类型的癌症干细胞中寻找高度保守的全球表型特征，以提供一种不依赖突变的癌症治疗方法。这将使我们能够靶向癌症干细胞，有效地将癌症作为一种“干性”疾病进行治疗，而与肿瘤组织类型无关。使用这种方法，我们确定了一个保守的表型弱点-癌症干细胞的克隆扩增和存活严格依赖于线粒体生物发生。有趣的是，FDA批准的几类抗生素抑制线粒体生物发生，这是一种已知的“副作用”，而这可以被利用为“治疗作用”。基于这一分析，我们现在表明，4至5种不同类别的FDA批准的药物可用于根除12种不同癌细胞系中的癌症干细胞，跨越8种不同的肿瘤类型（乳腺癌、DCIS、卵巢癌、前列腺癌、肺癌、胰腺癌、黑色素瘤和胶质母细胞瘤（脑））。这五类靶向抗生素包括：红霉素、四环素、甘氨酰环素、抗寄生虫药和氯霉素。功能数据显示，每种药物类别中的一种抗生素：阿奇霉素，多西环素，替加环素，pyrvinium双羟萘酸盐，以及氯霉素，作为概念验证。重要的是，这些药物中的许多对正常细胞无毒，可能会减少抗癌治疗的副作用。因此，我们现在建议将FDA批准的抗生素重新用于抗癌治疗，以治疗多种肿瘤类型的癌症，就像治疗传染病一样。这些药物类别也应该被考虑用于预防研究，特别是关注预防肿瘤复发和远处转移。最后，最近的多西环素和阿奇霉素（旨在靶向癌症相关感染，而不是癌细胞）的临床试验已经显示出对癌症患者的积极治疗效果，尽管它们根除癌症干细胞的能力尚未得到认可。
Here, we propose a new strategy for the treatment of early cancerous lesions and advanced metastatic disease, via the selective targeting of cancer stem cells (CSCs), a.k.a., tumor-initiating cells (TICs). We searched for a global phenotypic characteristic that was highly conserved among cancer stem cells, across multiple tumor types, to provide a mutation-independent approach to cancer therapy. This would allow us to target cancer stem cells, effectively treating cancer as a single disease of “stemness”, independently of the tumor tissue type. Using this approach, we identified a conserved phenotypic weak point – a strict dependence on mitochondrial biogenesis for the clonal expansion and survival of cancer stem cells. Interestingly, several classes of FDA-approved antibiotics inhibit mitochondrial biogenesis as a known “side-effect”, which could be harnessed instead as a “therapeutic effect”. Based on this analysis, we now show that 4-to-5 different classes of FDA-approved drugs can be used to eradicate cancer stem cells, in 12 different cancer cell lines, across 8 different tumor types (breast, DCIS, ovarian, prostate, lung, pancreatic, melanoma, and glioblastoma (brain)). These five classes of mitochondrially-targeted antibiotics include: the erythromycins, the tetracyclines, the glycylcyclines, an anti-parasitic drug, and chloramphenicol. Functional data are presented for one antibiotic in each drug class: azithromycin, doxycycline, tigecycline, pyrvinium pamoate, as well as chloramphenicol, as proof-of-concept. Importantly, many of these drugs are non-toxic for normal cells, likely reducing the side effects of anti-cancer therapy. Thus, we now propose to treat cancer like an infectious disease, by repurposing FDA-approved antibiotics for anti-cancer therapy, across multiple tumor types. These drug classes should also be considered for prevention studies, specifically focused on the prevention of tumor recurrence and distant metastasis. Finally, recent clinical trials with doxycycline and azithromycin (intended to target cancer-associated infections, but not cancer cells) have already shown positive therapeutic effects in cancer patients, although their ability to eradicate cancer stem cells was not yet appreciated.
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DOI：
10.1126/science.1260825
发表时间：
2015-01-02
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Tomasetti C;Vogelstein B
通讯作者：
Vogelstein B
影响因子：
10.3
作者：
Ferreri, Andres J. M.;Ponzoni, Maurilio;Dolcetti, Riccardo
通讯作者：
Dolcetti, Riccardo
影响因子：
0.4
作者：
Chu, D. J.;Yao, D. E.;Yu, Z. Y.
通讯作者：
Yu, Z. Y.
影响因子：
--
作者：
Rattan R;Ali Fehmi R;Munkarah A
通讯作者：
Munkarah A
影响因子：
50.3
作者：
Girotti MR;Lopes F;Preece N;Niculescu-Duvaz D;Zambon A;Davies L;Whittaker S;Saturno G;Viros A;Pedersen M;Suijkerbuijk BM;Menard D;McLeary R;Johnson L;Fish L;Ejiama S;Sanchez-Laorden B;Hohloch J;Carragher N;Macleod K;Ashton G;Marusiak AA;Fusi A;Brognard J;Frame M;Lorigan P;Marais R;Springer C
通讯作者：
Springer C