Chowdhury Kaushik, Sharma Ankit, Kumar Suresh, Gunjan Gyanesh K, Nag Alo, Mandal Chandi C
Department of Biochemistry, School of Life Sciences, Central University of RajasthanAjmer, India.
Department of Biochemistry, University of DelhiNew Delhi, India.
Front Pharmacol. 2017 Sep 5;8:593. doi: 10.3389/fphar.2017.00593. eCollection 2017.
Modern treatment strategies provide better overall survival in cancer patients, primarily by controlling tumor growth. However, off-target and systemic toxicity, tumor recurrence, and resistance to therapy are still inadvertent hurdles in current treatment regimens. Similarly, metastasis is another deadly threat to patients suffering from cancer. This has created an urgent demand to come up with new drugs having anti-metastatic potential and minimum side effects. Thus, this study was aimed at exploring the anti-proliferative and anti-metastatic potential of colocynth medicinal plant. Results from MTT assay, morphological visualization of cells and scratch assay indicated a role of ethanol and acetone extracts of fruit pulp of the colocynth plant in inhibiting cell viability, enhancing cell cytotoxicity and preventing cell migration in various cancer cell types, including breast cancer cell lines MCF-7 and MDA-MB-231, and cervical cancer cell line SiHa, subsequently having a low cytotoxic effect on mononuclear PBMC and macrophage J774A cells. Our study in metastatic MDA-MB-231 cells showed that both ethanol and acetone pulp extracts decreased transcript levels of the anti-apoptotic genes BCL2 and BCLXL, and a reverse effect was observed for the pro-apoptotic genes BAX and caspase 3. Additionally, enhanced caspase 3 activity and downregulated BCL2 protein were seen, indicating a role of these extracts in inducing apoptotic activity. Moreover, MDA-MB-231 cells treated with both these extracts demonstrated up-regulation of the epithelial gene keratin 19 and down-regulation of the mesenchymal genes, vimentin, -cadherin, Zeb1 and Zeb2 compared to control, suggesting a suppressive impact of these extracts in epithelial to mesenchymal transition (EMT). In addition, these extracts inhibited colony and sphere formation with simultaneous reduction in the transcript level of the stemness associated genes, BMI-1 and CD44. It was also found that both the plant extracts exhibited synergistic potential with the chemotherapeutic drug doxorubicin to inhibit cancer viability. Furthermore, GC-MS/MS analysis revealed the presence of certain novel compounds in both the extracts that are responsible for the anti-cancer role of the extracts. Overall, the results of this report suggest, for the first time, that colocynth fruit pulp extracts may block the proliferative as well as metastatic activity of breast cancer cells.
现代治疗策略主要通过控制肿瘤生长，提高了癌症患者的总体生存率。然而，脱靶效应、全身毒性、肿瘤复发和治疗耐药性仍是当前治疗方案中难以避免的障碍。同样，转移是癌症患者面临的另一致命威胁。这就迫切需要研发出具有抗转移潜力且副作用最小的新药。因此，本研究旨在探索药西瓜药用植物的抗增殖和抗转移潜力。MTT 法、细胞形态可视化和划痕试验结果表明，药西瓜植物果肉的乙醇提取物和丙酮提取物在抑制多种癌细胞类型（包括乳腺癌细胞系 MCF-7 和 MDA-MB-231，以及宫颈癌细胞系 SiHa）的细胞活力、增强细胞毒性和阻止细胞迁移方面发挥了作用，随后对单核 PBMC 和巨噬细胞 J774A 细胞的细胞毒性较低。我们对转移性 MDA-MB-231 细胞的研究表明，乙醇提取物和丙酮果肉提取物均降低了抗凋亡基因 BCL2 和 BCLXL 的转录水平，而促凋亡基因 BAX 和半胱天冬酶 3 则呈现相反的作用。此外，观察到半胱天冬酶 3 活性增强和 BCL2 蛋白下调，表明这些提取物在诱导凋亡活性中发挥了作用。此外，与对照组相比，用这两种提取物处理的 MDA-MB-231 细胞显示上皮基因角蛋白 19 上调，间充质基因波形蛋白、E-钙黏蛋白、Zeb1 和 Zeb2 下调，表明这些提取物对上皮-间充质转化（EMT）具有抑制作用。此外，这些提取物抑制了集落和球体形成，同时降低了干性相关基因 BMI-1 和 CD44 的转录水平。还发现这两种植物提取物与化疗药物阿霉素具有协同抑制癌症活力的潜力。此外，气相色谱-串联质谱分析显示，两种提取物中均存在某些新型化合物，这些化合物是提取物发挥抗癌作用的原因。总体而言，本报告的结果首次表明，药西瓜果肉提取物可能会阻断乳腺癌细胞的增殖和转移活性。
