Temozolomide induces senescence but not apoptosis in human melanoma cells.
Temozolomide induces senescence but not apoptosis in human melanoma cells.
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DOI：
10.1038/sj.bjc.6604017
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发表时间：
2007-11-05
影响因子：
8.8
通讯作者：
Hersey, P.
中科院分区：
文献类型：
--
作者：
Mhaidat, N. M.;Zhang, X. D.;Allen, J.;Avery-Kiejda, K. A.;Scott, R. J.;Hersey, P.
替莫唑胺（TMZ）是一种用于治疗黑色素瘤的DNA烷化剂，据信通过在DNA中鸟嘌呤的O 6位添加甲基来介导其作用。对该药剂的抗性可能部分是由于O 6-甲基鸟嘌呤-DNA甲基转移酶（MGMT）的活性。在本研究中，我们发现黑色素瘤细胞对TMZ的敏感性取决于它们的p53状态和MGMT水平。对生存力降低的潜在机制的分析表明，即使在TK 6淋巴瘤细胞中观察到显著水平的凋亡，也没有诱导凋亡的证据。黑色素瘤细胞的敏感性与p53依赖的G2/M细胞周期阻滞和诱导衰老有关。为了验证p53的作用，在pifithrin-α（一种p53抑制剂）存在下重复试验。这导致具有野生型p53的黑素瘤细胞的生存力增加，并且逆转了G2/M细胞周期停滞。奇怪的是，细胞凋亡在黑色素瘤中增加，但在TK 6淋巴瘤细胞中减少。这些结果与TMZ对黑素瘤相对无效的观点一致，这是由于p53激活导致的凋亡信号传导缺陷。凋亡信号传导缺陷的性质仍有待探讨。
Temozolomide (TMZ), a DNA alkylating agent used in the treatment of melanoma, is believed to mediate its effect by addition of a methyl group to the O6 position of guanine in DNA. Resistance to the agent may be in part due to the activity of O6-methylguanine-DNA methyl transferase (MGMT). In the present study, we show that sensitivity of melanoma cells to TMZ was dependent on their p53 status and levels of MGMT. Analysis of the mechanisms underlying reduced viability showed no evidence for induction of apoptosis even though marked levels of apoptosis was seen in TK6 lymphoma cells. Sensitivity of melanoma cells was associated with p53-dependent G2/M cell cycle arrest and induction of senescence. To verify the role of p53, the assays were repeated in presence of pifithrin-α, an inhibitor of p53. This resulted in increased viability of melanoma cells with wild-type p53 and reversed G2/M cell cycle arrest. Paradoxically, apoptosis was increased in melanoma but decreased as expected in TK6 lymphoma cells. These results are consistent with the view that TMZ is relatively ineffective against melanoma due to defective apoptotic signalling resulting from activation of p53. The nature of the defects in apoptotic signalling remains to be explored.
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DOI：
10.1073/pnas.92.20.9363
发表时间：
1995-09-26
影响因子：
11.1
作者：
DIMRI, GP;LEE, XH;CAMPISI, J
通讯作者：
CAMPISI, J
影响因子：
11.5
作者：
Plummer, ER;Middleton, MR;Curtin, NJ
通讯作者：
Curtin, NJ
影响因子：
56.9
作者：
Villunger, A;Michalak, EM;Strasser, A
通讯作者：
Strasser, A
影响因子：
6.4
作者：
Nihal, M;Ahmad, N;Wood, GS
通讯作者：
Wood, GS
影响因子：
8.8
作者：
Günther, W;Pawlak, E;Damasceno, R;Arnold, H;Terzis, AJ
通讯作者：
Terzis, AJ