Potikanond Saranyapin, Sookkhee Siriwoot, Na Takuathung Mingkwan, Mungkornasawakul Pitchaya, Wikan Nitwara, Smith Duncan R, Nimlamool Wutigri
Department of Pharmacology, Faculty of Medicine, Chiang Mai UniversityChiang Mai, Thailand.
Department of Microbiology, Faculty of Medicine, Chiang Mai UniversityChiang Mai, Thailand.
Front Pharmacol. 2017 Sep 11;8:630. doi: 10.3389/fphar.2017.00630. eCollection 2017.
(KP) has been traditionally used as a folk remedy to treat several diseases including cancer, and several studies have reported cytotoxic activities of extracts of KP against a number of different cancer cell lines. However, many aspects of the molecular mechanism of action of KP remain unclear. In particular, the ability of KP to regulate cancer cell growth and survival signaling is still largely unexplored. The current study aimed to investigate the effects of KP on cell viability, cell migration, cell invasion, cell apoptosis, and on signaling pathways related to growth and survival of cervical cancer cells, HeLa. We discovered that KP reduced HeLa cell viability in a concentration-dependent manner. The potent cytotoxicity of KP against HeLa cells was associated with a dose-dependent induction of apoptotic cell death as determined by flow cytometry and observation of nuclear fragmentation. Moreover, KP-induced cell apoptosis was likely to be mediated through the intrinsic apoptosis pathway since caspase 9 and caspase 7, but not BID, were shown to be activated after KP exposure. Based on the observation that KP induced apoptosis in HeLa cell, we further investigated the effects of KP at non-cytotoxic concentrations on suppressing signal transduction pathways relevant to cell growth and survival. We found that KP suppressed the MAPK and PI3K/AKT signaling pathways in cells activated with EGF, as observed by a significant decrease in phosphorylation of ERK1/2, Elk1, PI3K, and AKT. The data suggest that KP interferes with the growth and survival of HeLa cells. Consistent with the inhibitory effect on EGF-stimulated signaling, KP potently suppressed the migration of HeLa cells. Concomitantly, KP was demonstrated to markedly inhibit HeLa cell invasion. The ability of KP in suppressing the migration and invasion of HeLa cells was associated with the suppression of matrix metalloproteinase-2 production. These data strongly suggest that KP may slow tumor progression and metastasis in patients with cervical cancer. Taken together, the present report provides accumulated evidence revealing the potent anti-cancer activities of against cervical cancer HeLa cells, and suggests its potential use as an alternative way for cervical cancer prevention and therapy.
KP传统上作为一种民间疗法用于治疗包括癌症在内的多种疾病,并且多项研究报道了KP提取物对多种不同癌细胞系具有细胞毒性活性。然而,KP作用的分子机制的许多方面仍不清楚。特别是,KP调节癌细胞生长和存活信号的能力在很大程度上仍未被探索。当前的研究旨在调查KP对子宫颈癌细胞HeLa的细胞活力、细胞迁移、细胞侵袭、细胞凋亡以及与生长和存活相关的信号通路的影响。我们发现KP以浓度依赖的方式降低HeLa细胞活力。通过流式细胞术和核碎裂观察确定,KP对HeLa细胞的强细胞毒性与凋亡细胞死亡的剂量依赖性诱导相关。此外,KP诱导的细胞凋亡可能通过内源性凋亡途径介导,因为在KP暴露后显示半胱天冬酶9和半胱天冬酶7被激活,而BID未被激活。基于KP诱导HeLa细胞凋亡的观察结果,我们进一步研究了非细胞毒性浓度的KP对抑制与细胞生长和存活相关的信号转导通路的影响。我们发现,如通过ERK1/2、Elk1、PI3K和AKT磷酸化的显著降低所观察到的,KP抑制了用表皮生长因子(EGF)激活的细胞中的丝裂原活化蛋白激酶(MAPK)和磷脂酰肌醇-3激酶/蛋白激酶B(PI3K/AKT)信号通路。数据表明KP干扰HeLa细胞的生长和存活。与对EGF刺激信号的抑制作用一致,KP有力地抑制了HeLa细胞的迁移。同时,已证明KP显著抑制HeLa细胞侵袭。KP抑制HeLa细胞迁移和侵袭的能力与基质金属蛋白酶-2产生的抑制相关。这些数据强烈表明KP可能减缓子宫颈癌患者的肿瘤进展和转移。综上所述,本报告提供了累积证据,揭示了KP对子宫颈癌HeLa细胞具有强大的抗癌活性,并表明其作为子宫颈癌预防和治疗的替代方法的潜在用途。
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