Odonkor Charles A, Achilefu Samuel
Department of Radiology, Washington University School of Medicine, St Louis, MO 63110, USA.
Cancer Invest. 2009 May;27(4):417-29. doi: 10.1080/07357900802438585.
In spite of compelling evidence-implicating caspases in drug-induced apoptosis, how tumors modulate caspase expression and activity to overcome the cytotoxicity of anticancer agents is not fully understood. To address this issue, we investigated the role of caspases-3 and caspase-7 in determining the response of breast and lung tumor cell lines to chemotherapy. We found that an early and late apoptotic response correlated with weak and strong cellular caspase-activation, respectively. The results highlight an underappreciated relationship of temporal apoptotic response with caspase-activation and drug resistance. Moreover, the extent of tumor growth restoration after drug withdrawal was dependent on the degree of endogenous blockage of caspase-3 and caspase-7 cleavages. This points to an unrecognized role of caspase modulation in tumor recurrence and suggests that targeting caspase cleavage is a rational approach to increasing potency of cancer drugs.
尽管有确凿证据表明半胱天冬酶与药物诱导的细胞凋亡有关，但肿瘤如何调节半胱天冬酶的表达和活性以克服抗癌药物的细胞毒性仍未完全明确。为解决这一问题，我们研究了半胱天冬酶 -3 和半胱天冬酶 -7 在决定乳腺癌和肺癌细胞系对化疗反应中的作用。我们发现早期和晚期凋亡反应分别与细胞半胱天冬酶激活的强弱相关。这些结果凸显了凋亡反应时间与半胱天冬酶激活及耐药性之间未被充分认识的关系。此外，停药后肿瘤生长恢复的程度取决于半胱天冬酶 -3 和半胱天冬酶 -7 切割的内源性阻断程度。这表明半胱天冬酶调节在肿瘤复发中存在未被认识的作用，并提示靶向半胱天冬酶切割是提高抗癌药物效力的合理方法。
