Targeting acid sphingomyelinase with anti-angiogenic chemotherapy.
Targeting acid sphingomyelinase with anti-angiogenic chemotherapy.
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DOI：
10.1016/j.cellsig.2016.09.010
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发表时间：
2017-01
影响因子：
4.8
通讯作者：
Haimovitz-Friedman A
中科院分区：
文献类型：
--
作者：
Jacobi J;García-Barros M;Rao S;Rotolo JA;Thompson C;Mizrachi A;Feldman R;Manova K;Bielawska A;Bielawska J;Fuks Z;Kolesnick R;Haimovitz-Friedman A
尽管前景看好，但联合使用抗血管生成药物和常规抗癌药物在临床试验中产生的治疗效果有限，这可能是因为抗血管生成组织反应的机制仍然只有部分了解。在这里，我们定义了一个新的范例，在这个范例中，抗血管生成药物可以通过靶向内皮酸性鞘磷脂酶(ASMase)信号转导通路来用于肿瘤的化疗增敏。我们在几分钟内证明了紫杉醇和依托泊苷，而不是顺铂，会导致ASMase介导的内皮损伤。这种快速反应是人结肠癌异种移植瘤完全反应和生长延迟所必需的。而血管内皮生长因子抑制ASMase，抗VEGFR2抗体抑制ASMase，促进ASMase+/+中的内皮细胞凋亡和药物诱导的肿瘤反应，但在Asmase−/−中无此作用。只有在化疗前1-2小时给药，而不是在化疗前或化疗后的其他时间，这种化疗增敏才会发生。我们的研究表明，精确的抗血管生成药物联合ASMase靶向抗癌药物的应用可能会优化全身化疗的抗肿瘤效果。这一策略值得在未来的临床试验中进行评估。
Despite great promise, combining anti-angiogenic and conventional anti-cancer drugs has produced limited therapeutic benefit in clinical trials, presumably because mechanisms of anti-angiogenic tissue response remain only partially understood. Here we define a new paradigm, in which anti-angiogenic drugs can be used to chemosensitize tumors by targeting the endothelial acid sphingomyelinase (ASMase) signal transduction pathway. We demonstrate that paclitaxel and etoposide, but not cisplatin, confer ASMase-mediated endothelial injury within minutes. This rapid reaction is required for human HCT-116 colon cancer xenograft complete response and growth delay. Whereas VEGF inhibits ASMase, anti-VEGFR2 antibodies de-repress ASMase, enhancing endothelial apoptosis and drug-induced tumor response in asmase+/+, but not in asmase−/−, hosts. Such chemosensitization occurs only if the anti-angiogenic drug is delivered 1–2 hours before chemotherapy, but at no other time prior to or post chemotherapy. Our studies suggest that precisely-timed administration of anti-angiogenic drugs in combination with ASMase-targeting anti-cancer drugs is likely to optimize anti-tumor effects of systemic chemotherapy. This strategy warrants evaluation in future clinical trials.
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影响因子：
4.8
作者：
Schissel, SL;Schuchman, EH;Tabas, I
通讯作者：
Tabas, I
影响因子：
3.7
作者：
Separovic, Duska;Semaan, Louie;Luberto, Chiara
通讯作者：
Luberto, Chiara
DOI：
10.1387/ijdb.103217fb
发表时间：
2011-01-01
期刊：
The International journal of developmental biology
影响因子：
--
作者：
Kerbel, Robert
通讯作者：
Kerbel, Robert
影响因子：
4.8
作者：
Rotolo, JA;Zhang, JJ;Kolesnick, R
通讯作者：
Kolesnick, R
影响因子：
3.7
作者：
Stancevic B;Varda-Bloom N;Cheng J;Fuller JD;Rotolo JA;García-Barros M;Feldman R;Rao S;Weichselbaum RR;Harats D;Haimovitz-Friedman A;Fuks Z;Sadelain M;Kolesnick R
通讯作者：
Kolesnick R