β-Lapachone and its iodine derivatives cause cell cycle arrest at G2/M phase and reactive oxygen species-mediated apoptosis in human oral squamous cell carcinoma cells
β-Lapachone and its iodine derivatives cause cell cycle arrest at G2/M phase and reactive oxygen species-mediated apoptosis in human oral squamous cell carcinoma cells
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DOI：
10.1016/j.freeradbiomed.2018.07.022
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发表时间：
2018-10-01
影响因子：
7.4
通讯作者：
Gurgel Rocha, Clarissa Araujo
中科院分区：
文献类型：
--
作者：
Dias, Rosane Borges;Sacramento de Araujo, Tais Bacelar;Gurgel Rocha, Clarissa Araujo
β-拉帕醌是一种天然的萘醌，最初从紫藤（TabebuiavellanedaeLor，紫藤科）的树皮中获得，并且其在人癌细胞中的治疗潜力已经在几项研究中进行了评估。在这项研究中，我们研究了β-拉帕醌及其3-碘衍生物（3-I-alpha-拉帕醌和3-I-beta-拉帕醌）对人口腔鳞状细胞癌细胞的细胞增殖，细胞死亡和癌症相关基因表达的影响。β-拉帕酮及其3-碘衍生物对不同类型的人癌细胞系显示出有效的细胞毒性。事实上，用这些化合物处理诱导细胞周期停滞在G（2）/M期，随后是核小体间DNA片段化，并引起磷脂酰丝氨酸外化、半胱天冬酶-8和-9活化、线粒体膜去极化、活性氧（ROS）产生和凋亡细胞死亡形态的显著增加。化合物诱导的细胞凋亡通过用泛半胱天冬酶抑制剂（Z-VAD-FMK）和抗氧化剂（N-乙酰基-L-半胱氨酸）预处理来防止。在体内，β-拉帕酮及其3-碘衍生物显着降低肿瘤负荷，并没有改变任何生物化学，血液学，或动物的组织学参数。总的来说，β-拉帕酮及其3-碘衍生物显示出有希望的细胞毒活性，由于它们能够诱导细胞周期停滞在G（2）/M期，并促进caspase和ROS介导的凋亡。此外，β-拉帕酮及其3-碘衍生物能够抑制体内肿瘤生长，表明这些化合物可能是新的抗肿瘤候选药物。
beta-Lapachone is a natural naphthoquinone originally obtained from the bark of the purple Ipe (Tabebuia avellanedae Lor, Bignoniaceae) and its therapeutic potential in human cancer cells has been evaluated in several studies. In this study, we examined the effects of beta-lapachone and its 3-iodine derivatives (3-I-alpha-lapachone and 3-I-beta-lapachone) on cell proliferation, cell death, and cancer-related gene expression in human oral squamous cell carcinoma cells. beta-Lapachone and its 3-iodine derivatives showed potent cytotoxicity against different types of human cancer cell lines. Indeed, treatment with these compounds induced cell cycle arrest at G(2)/M phase, followed by internucleosomal DNA fragmentation, and caused significant increases in phosphatidylserine externalization, caspase-8 and -9 activation, mitochondrial membrane depolarization, reactive oxygen species (ROS) production, and apoptotic cell death morphology. The apoptosis induced by the compounds was prevented by pretreatment with a pan-caspase inhibitor (Z-VAD-FMK) and an antioxidant (N-acetyl-L-cysteine). In vivo, beta-lapachone and its 3-iodine derivatives significantly reduced tumor burden and did not alter any of the biochemical, hematological, or histological parameters of the animals. Overall, beta-lapachone and its 3-iodine derivatives showed promising cytotoxic activity due to their ability to induce cell cycle arrest at G(2)/M phase and promote caspase-and ROS-mediated apoptosis. In addition, beta-lapachone and its 3-iodine derivatives were able to suppress tumor growth in vivo, indicating that these compounds may be new antitumor drug candidates.