Gavrilov Vladimir, Lavrenkov Konstantin, Ariad Samuel, Shany Shraga
Department of Clinical Biochemistry and Pharmacology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel
Institute of Oncology, Soroka University Medical Center, Beer Sheva, Israel.
Anticancer Res. 2014 Nov;34(11):6565-72.
To enhance the anticancer activity of vinorelbine, cisplatin and ionizing radiation (IR) combination against non-small cell lung cancer (NSCLC) cells by co-administration of sodium valproate (VPA), a histone deacetylase inhibitor, and to elucidate molecular events underpinning treatment efficacy.
The NSCLC A549 cell line was treated with cisplatin (0.2 μg/ml), vinorelbine (2 nM), VPA (1 mM) and IR (2.5 Gy) alone, or in combination. Cell proliferation, cell-cycle distribution, apoptosis, and levels of DNA double-strand breaks, activated DNA damage checkpoint kinases pCHK1, pCHK2, cell-cycle inhibitors p21CIP1/WAF1 and p27KIP1 were assessed.
VPA markedly enhanced the DNA-damaging effect of the cisplatin-vinorelbine-IR combination and induced increased DSBs, and expression of pCHK2, pCHK1, p21CIP1/WAF1 and p27KIP1. These molecular changes led to cell-cycle arrest and increased apoptosis and consequently markedly curtailed cancer cell growth.
VPA markedly enhances the anticancer activity of cisplatin-vinorelbine-IR combination. This finding has translational implications for enhancing the efficacy of anticancer treatment and for reducing side-effects by reducing doses of radiation and drugs.
通过联合使用组蛋白脱乙酰酶抑制剂丙戊酸钠（VPA）来增强长春瑞滨、顺铂和电离辐射（IR）联合方案对非小细胞肺癌（NSCLC）细胞的抗癌活性，并阐明治疗效果背后的分子机制。
NSCLC A549细胞系分别单独或联合使用顺铂（0.2μg/ml）、长春瑞滨（2nM）、VPA（1mM）和IR（2.5Gy）进行处理。评估细胞增殖、细胞周期分布、凋亡以及DNA双链断裂水平、活化的DNA损伤检查点激酶pCHK1、pCHK2、细胞周期抑制剂p21CIP1/WAF1和p27KIP1的水平。
VPA显著增强了顺铂-长春瑞滨-IR联合方案的DNA损伤效应，并诱导双链断裂增加，以及pCHK2、pCHK1、p21CIP1/WAF1和p27KIP1的表达增加。这些分子变化导致细胞周期停滞和凋亡增加，从而显著抑制癌细胞生长。
VPA显著增强了顺铂-长春瑞滨-IR联合方案的抗癌活性。这一发现对于提高抗癌治疗效果以及通过减少放疗和药物剂量来降低副作用具有转化意义。
