Nair Bhagyalakshmi, Anto Ruby John, M Sabitha, Nath Lekshmi R
Amrita School of Pharmacy, Amrita Vishwa Vidyapeetham, AIMS Health Science Campus, Ponekkara P.O., Kochi, Kerala 682041, India.
Division of Cancer Research, Rajiv Gandhi Center for Biotechnology, Thycaud, Thiruvananthapuram, Kerala- 695014, India. Introduction.
Adv Pharm Bull. 2020 Jul;10(3):472-476. doi: 10.34172/apb.2020.058. Epub 2020 May 11.
Sorafenib is the sole FDA approved drug conventionally used for the treatment of advanced hepatocellular carcinoma (HCC). Despite of the beneficial use of sorafenib in the treatment of HCC, multidrug resistance still remains a challenge. HCC is inherently known as chemotherapy resistant tumor due to P-glycoprotein (P-gp)-mediated multidrug resistance. We studied the interaction energy of kaempferol with human multidrug resistance protein-1 (RCSB PDB ID: 2CBZ) using method with the help of BIOVIA Discovery Studio. HepG2 and N1S1 liver cancer cell lines were treated in suitable cell culture media to evaluate the efficacy of kaempferol in chemo-sensitizing liver cancer cells towards the effect of sorafenib. Cell viability study was performed by MTT assay. analysis of kaempferol showed best docking score of 23.14 with Human Multi Drug Resistant Protein-1 (RCSB PDB ID: 2CBZ) compared with positive control verapamil. In condition, combination of sub-toxic concentrations of both kaempferol and sorafenib produced 50% cytotoxicity with concentration of 2.5 µM each which indicates that kaempferol has the ability to reverse the MDR by decreasing the over-expression of P-gp. Kaempferol is able to sensitize the HepG2 and N1S1 against the sub-toxic concentration of sorafenib. Hence, we consider that the efficacy of sorafenib chemotherapy can be enhanced by the significant approach of combining the sub-toxic concentrations of sorafenib with kaempferol. Thus, kaempferol can be used as a better candidate molecule along with sorafenib for enhancing its efficacy, if validated through preclinical studies.
索拉非尼是美国食品药品监督管理局（FDA）唯一批准的传统上用于治疗晚期肝细胞癌（HCC）的药物。尽管索拉非尼在治疗HCC方面有有益作用，但多药耐药性仍然是一个挑战。由于P-糖蛋白（P-gp）介导的多药耐药性，HCC本质上被认为是化疗耐药性肿瘤。我们借助BIOVIA Discovery Studio软件，使用[具体方法]研究了山柰酚与人多药耐药蛋白-1（RCSB PDB ID：2CBZ）的相互作用能。在合适的细胞培养基中处理HepG2和N1S1肝癌细胞系，以评估山柰酚对肝癌细胞对索拉非尼作用的化疗增敏效果。通过MTT法进行细胞活力研究。与阳性对照维拉帕米相比，山柰酚的[具体分析]显示其与人类多药耐药蛋白-1（RCSB PDB ID：2CBZ）的最佳对接分数为23.14。在该条件下，山柰酚和索拉非尼的亚毒性浓度组合在各自浓度为2.5 µM时产生了50%的细胞毒性，这表明山柰酚有能力通过降低P-gp的过度表达来逆转多药耐药性。山柰酚能够使HepG2和N1S1对索拉非尼的亚毒性浓度敏感。因此，我们认为将索拉非尼的亚毒性浓度与山柰酚联合使用这一重要方法可以提高索拉非尼化疗的疗效。因此，如果通过临床前研究得到验证，山柰酚可以作为与索拉非尼联合使用以提高其疗效的更好候选分子。
