Unit of Excellence in Cancer Genetics, Department of Genetics, Centre for Excellence in Genomic Sciences, School of Biological Sciences, Madurai Kamaraj University, Madurai, India.
Unit of Excellence in Cancer Genetics, Department of Genetics, Centre for Excellence in Genomic Sciences, School of Biological Sciences, Madurai Kamaraj University, Madurai, India.
Toxicol In Vitro. 2021 Aug;74:105152. doi: 10.1016/j.tiv.2021.105152. Epub 2021 Mar 24.
Elevated expression of YY1 is known to confer anti-apoptotic phenotype and hence is an attractive target for cancer therapeutics. In a repurpose screening, towards the identification of the inhibitors of YY1 regulated transcription in gastric cancer cells, the calcium channel blockers lercanidipine and amlodipine have been identified to inhibit YY1 more efficiently. We further probed these calcium channel blockers for their potential feature of alleviating the drug resistance in gastric cancer cells. Lercanidipine and amlodipine were found to show an enhanced effect with doxorubicin in inhibiting the growth of gastric cancer cells. While doxorubicin was identified to activate the pathways TGF-β and ERK/MAPK, lercanidipine was found to inhibit these pathways. This being the molecular mechanism behind the identified advantage of lercanidipine and amlodipine in sensitizing gastric cancer cells to doxorubicin. In multiple cellular models from different lineages, the cells with less sensitivity to doxorubicin were found to have the inherent activation of ERK/MAPK and TGF-β pathways. Also, we have identified that doxorubicin, in combination with any of the calcium channel blockers, could inhibit the potential of cellular proliferation and spheroid formation in gastric cancer cells. The current study shows the usefulness of lercanidipine and amlodipine for the targeted and combinatorial therapeutics of gastric cancer and specifically to improve the efficiency of doxorubicin.
已知 YY1 的高表达赋予了抗细胞凋亡表型，因此是癌症治疗的一个有吸引力的靶点。在重新定位筛选中，为了鉴定在胃癌细胞中调节 YY1 转录的抑制剂，已经发现钙通道阻滞剂乐卡地平（lercanidipine）和氨氯地平（amlodipine）更有效地抑制 YY1。我们进一步探究了这些钙通道阻滞剂在缓解胃癌细胞耐药性方面的潜在特性。发现乐卡地平和氨氯地平与阿霉素（doxorubicin）联合使用时，能更有效地抑制胃癌细胞的生长。虽然阿霉素被鉴定为激活 TGF-β和 ERK/MAPK 通路，但乐卡地平被发现抑制了这些通路。这就是乐卡地平和氨氯地平在增敏胃癌细胞对阿霉素方面具有优势的分子机制。在来自不同谱系的多种细胞模型中，发现对阿霉素敏感性较低的细胞固有地激活了 ERK/MAPK 和 TGF-β通路。此外，我们还确定了阿霉素与任何一种钙通道阻滞剂联合使用，都可以抑制胃癌细胞的增殖和球体形成的潜力。本研究表明乐卡地平和氨氯地平可用于胃癌的靶向和联合治疗，特别是提高阿霉素的效率。
