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首页> 外文期刊>Life sciences >Differential effects of non-genotoxic carcinogens and proliferating agents on cell growth, survival and apoptosis in hepatic cells in vitro.
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Differential effects of non-genotoxic carcinogens and proliferating agents on cell growth, survival and apoptosis in hepatic cells in vitro.

机译：非遗传毒性致癌物和增殖剂对体外肝细胞生长，存活和凋亡的差异作用。

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Many nongenotoxic carcinogen's (ngc) produce hyperplastic lesions from which neoplastic foci may arise. Modulation of the rate of apoptosis by some ngc's within these lesions may be critical to their mechanism of tumour promotion but some may be cytotoxic. To establish if these compounds are apoptotic or necrotic in vitro, three ngc's (12-0-tetradecanoyl phorbol-13-acetate (TPA); nickel, and di(2-ethylhexyl-phthalate (DEHP), two noncarcinogenic hepatoproliferating agents (1,4-dichlorobenzene (DCB; HGF) and an in vitro genotoxic reference compound (7-hydroxy-2-acetylaminofluorene (70H2AAF) were used to induce mitogenic or growth responses in two liver cell-lines HepG2 and JTC-15. MTT and 3H-thymidine incorporation assays were used to measure cell growth and DNA replicative activity respectively. Rates of apoptosis were assayed using FITC-annexin V with propidium iodide staining and flow cytometry. Responses in HepG2 cells were HGF (proliferation at > or = 3 ng/ml), TPA (cell growth at > or = 8 ng/ml), DEHP (proliferation at > or = 0.05 microg/ml). NiCl2 and 70H-2AAF were cytotoxic above 0.001 microg/ml and 100 ng/ml respectively. An equivocal result was obtained for DCB. Responses in JTC-15 cells were HGF (proliferation, 3 ng/ml), TPA (DNA replication, 10 ng/ml), and DEHP (cell mass, 2.5 microl/ml). NiCl2 and 70H-2AAF were cytotoxic above 0.01 microg/ml and 110 mg/ml respectively. Equivocal results were obtained for DCB. In flow cytometry assays apoptotic and necrotic populations were not clearly separable. Approximate rates of apoptosis in HepG2 were: control 8.7%; DEHP, 10.19%. NiCl2, 12.67%; 70H2AAF, 16.56%; TPA, 19.72%; HGF, 23.73%; DCB, 24.59%; positive apoptotic control (taxol) 26.94%. These data show apoptosis was increased in chemically activated populations of HepG2. The ngc, DEHP, unexpectedtly produced proliferation in HepG2 and almost totally suppressed apoptosis in vitro in HepG2 relative to the non-carcinogenic hepatoproliferators. The rate of apoptosis induced by the ngc TPA was not considered to be sufficiently different to the rates of apoptosis induced by the noncarcinogenic hepatoproliferators. The results emphasize the importance of considering necrotic reactions from effects on apoptosis in detecting non-genotoxic carcinogens.
机译：许多非遗传毒性致癌物（ngc）产生增生性病变，可能会形成肿瘤灶。这些病变中某些ngc对细胞凋亡速率的调节可能对它们促进肿瘤的机制至关重要，但有些可能具有细胞毒性。为了确定这些化合物在体外是凋亡的还是坏死的，使用了三种ngc（12-0-十四烷酰佛波醇13-乙酸盐（TPA）;镍和邻苯二甲酸二（2-乙基己基酯）（DEHP），两种非致癌性肝增殖剂（1，使用4-二氯苯（DCB; HGF）和体外遗传毒性参考化合物（7-羟基-2-乙酰氨基芴（70H2AAF））在两种肝细胞系HepG2和JTC-15，MTT和3H-中诱导有丝分裂或生长反应。胸腺嘧啶核苷掺入法分别测量细胞生长和DNA复制活性，FITC-annexin V碘化丙啶染色和流式细胞术检测细胞凋亡率，HepG2细胞的反应为HGF（增殖≥3 ng / ml）。 ，TPA（细胞生长>或= 8 ng / ml），DEHP（细胞增殖>或= 0.05 microg / ml），NiCl2和70H-2AAF对细胞的毒性分别高于0.001 microg / ml和100 ng / ml。获得了DCB信号，JTC-15细胞的反应为HGF（增殖，3 ng / ml），TPA（DN）复制（10 ng / ml）和DEHP（细胞质量，2.5微升/ ml）。 NiCl2和70H-2AAF分别具有0.01 microg / ml和110 mg / ml以上的细胞毒性。对于DCB获得了模棱两可的结果。在流式细胞仪检测中，凋亡和坏死种群并没有明显分离。 HepG2中的凋亡率约为：对照组8.7％; DEHP，10.19％。氯化镍，12.67％; 70H2AAF，16.56％; TPA，19.72％; HGF，23.73％; DCB，24.59％;凋亡控制阳性（紫杉醇）为26.94％。这些数据表明，在化学活化的HepG2群体中凋亡增加。 ngc DEHP意外地在HepG2中产生增殖，并且相对于非致癌性肝细胞增生药而言，在HepG2中几乎完全抑制了细胞凋亡。 ngc TPA诱导的凋亡率与非致癌性肝细胞增生药诱导的凋亡率没有足够的差异。结果强调了在检测非遗传毒性致癌物时考虑对细胞凋亡影响的坏死反应的重要性。

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