Induction of apoptosis by cidofovir in human papillomavirus (HPV)-positive cells
Induction of apoptosis by cidofovir in human papillomavirus (HPV)-positive cells
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DOI：
10.3727/096504001108747855
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发表时间：
2001-01-01
影响因子：
3.1
通讯作者：
De Clercq, E
中科院分区：
文献类型：
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作者：
Andrei, G;Snoeck, R;De Clercq, E
HPMPC(cidofovir，CDV)是一种广谱抗人乳头瘤病毒(HPV)等DNA病毒活性的无环核苷膦(ANP)。在多项临床研究中，HPMPC已被证明在治疗HPV相关疾病方面有效。在体外，HPMPC处理HPV阳性细胞(与正常原代人角质形成细胞相比)导致了对细胞增殖的浓度和时间依赖性的抑制。我们现在已经评估了这种化合物诱导细胞死亡的机制。不同的细胞凋亡参数，即(I)诱导CPP32(caspase-3)蛋白酶活性，(Ii)磷脂酰丝氨酸(PS)从质膜内层移位到外层，(Iii)核基质蛋白(NMP)的解体，(Iv)DNA片段化，(V)细胞周期分析后处于凋亡期的细胞数量，表明CDV处理后细胞死亡的机制是以细胞凋亡为基础的。Annexin V染色显示，HPV阳性细胞的凋亡诱导与活细胞百分率的下降有关，而原代培养的人角质形成细胞(PHK)活细胞百分率无明显变化。此外，观察到HPMPC处理的细胞在细胞周期的S期显著积累。细胞凋亡诱导和S时相阻滞呈浓度和时间依赖性。HPMPC诱导HPV阳性细胞的凋亡与肿瘤抑制蛋白P53和细胞周期蛋白依赖性激酶抑制因子p21/WAF-1的积聚有关。由于HPMPC已被证明以时间和浓度依赖的方式诱导许多HPV阳性细胞系的凋亡，HPMPC观察到的患者乳头状瘤病变的消退可能至少部分归因于诱导细胞凋亡。
HPMPC (cidofovir, CDV) is an acyclic nucleoside phosphonate (ANP) with broad-spectrum activity against DNA viruses, including human papillomavirus (HPV). HPMPC has proved to be effective in the treatment of HPV-associated disease in several clinical investigations. In vitro, treatment of HPV-positive cells (compared with normal primary human keratinocytes) with HPMPC has resulted in a concentration- and time-dependent inhibition of cell proliferation. We have now evaluated the mechanism by which this compound induces cell death. Different parameters of apoptosis, that is, (i) induction of CPP32 (caspase-3) protease activity, (ii) translocation of phosphatidylserine (PS) from the inner part of the plasma membrane to the outer layer, (iii) disintegration of the nuclear matrix protein (NMP), (iv) DNA fragmentation, (v) number of cells in apoptotic phase following cell cycle analysis, showed that the mechanism of cell death following treatment with CDV is based on apoptosis. Annexin V staining showed that induction of apoptosis in HPV-positive cells was correlated with a decrease in the percentage of viable cells, while no significant changes in the percentages of living cells were noted in primary human keratinocytes (PHK) cell cultures. Furthermore, a remarkable accumulation of HPMPC-treated cells in the S phase of the cell cycle was observed. Apoptosis induction and S phase arrest were concentration and time dependent. Induction of apoptosis in HPV-positive cells by HPMPC was associated with accumulation of the tumor suppressor protein p53 and the cyclin-dependent kinase inhibitor p21/WAF-1. As HPMPC has proved to induce apoptosis, in a time- and concentration-dependent manner, in a number of HPV-positive cell lines, the regression of papillomatous lesions observed with HPMPC in patients may be due, at least in part, to the induction of apoptosis.