Fulda S, Friesen C, Debatin K M
University Children's Hospital, Ulm, Germany.
Klin Padiatr. 1998 Jul-Aug;210(4):148-52. doi: 10.1055/s-2008-1043870.
Recent experimental evidence suggests that apoptosis pathways such as the CD95 system are an important mediator of chemotherapy-induced apoptosis in various tumor cell lines. Therapeutic concentrations of cytotoxic drugs induce CD95 and CD95-L that mediates apoptosis via an autocrine/paracrine loop by crosslinking CD95. Interfering with CD95-L/receptor interaction by antagonistic antibodies to the receptor or by inhibition of CD95-L expression strongly reduces apoptosis. Drug-induced apoptosis critically depends on activation of caspases since apoptosis is almost completely abrogated by the caspase inhibitor zVAD-fmk. The receptor apical caspase FLICE/MACH (caspase-8) and the downstream caspase CPP32 (caspase-3) are cleaved resulting in processing of substrates such as the nuclear enzyme PARP. In addition, the response to cytotoxic drugs is modulated by pro- and antiapoptotic proteins of the Bcl-2 family and p53. Defects in apoptosis pathways, e.g. deficient upregulation of CD95-L, downregulation of CD95 expression or blockade of caspase activation may confer resistance to cytotoxic drug treatment. Thus, chemosensitivity of tumor cells depends on intact apoptosis pathways such as the CD95 system that are activated by chemotherapeutic drugs. These findings may have implications for drug sensitivity and resistance of tumor cells.
最近的实验证据表明，诸如CD95系统之类的凋亡途径是化疗诱导多种肿瘤细胞系凋亡的重要介质。细胞毒性药物的治疗浓度可诱导CD95和CD95-L，后者通过交联CD95经自分泌/旁分泌环介导凋亡。用抗受体拮抗抗体或通过抑制CD95-L表达干扰CD95-L/受体相互作用可强烈减少凋亡。药物诱导的凋亡关键取决于半胱天冬酶的激活，因为凋亡几乎被半胱天冬酶抑制剂zVAD-fmk完全消除。受体顶端半胱天冬酶FLICE/MACH（半胱天冬酶-8）和下游半胱天冬酶CPP32（半胱天冬酶-3）被切割，导致诸如核酶PARP等底物的加工。此外，对细胞毒性药物的反应受Bcl-2家族和p53的促凋亡和抗凋亡蛋白调节。凋亡途径的缺陷，例如CD95-L上调不足、CD95表达下调或半胱天冬酶激活受阻，可能导致对细胞毒性药物治疗产生耐药性。因此，肿瘤细胞的化学敏感性取决于完整的凋亡途径，如被化疗药物激活的CD95系统。这些发现可能对肿瘤细胞的药物敏感性和耐药性有影响。
