Rauf Abdur, Khan Ajmal, Abu-Izneid Tareq, Alhumaydhi Fahad A, Bawazeer Saud, Raza Muslim, Khan Haroon, Patel Seema, Al-Harrasi Ahmed
Department of Chemistry, University of Swabi, Anbar-23561, Khyber Pakhtunkhwa, Pakistan.
Natural and Medical Sciences Research Center, University of Nizwa, Birkat-ul-Mouz 616, Nizwa, Oman.
Anticancer Agents Med Chem. 2021;21(15):2089-2097. doi: 10.2174/1871520621666210112113127.
Cancer being a genetically heterogeneous and complex disease and the available therapies are not very effective, rendering them the predominant cause of mortality across the world. The discovery of new anticancer drugs with higher efficacy and milder side effects is a great challenge for health professionals.
The current study focused on the anticancer potential of two known dimeric napthoquiones, diospyrin (1) and 8-hydroxydiospyrin (2) isolated from the roots of Diospyros lotus.
In vitro Epstein-Barr-Virus (EVA) an early antigen activation assay was used to evaluate the antitumor potential of tested compounds followed by a two-stage carcinogenesis assay on mouse skin for anti-carcinogenic effect. Compounds were also assessed for their multidrug resistance reversal potential. The in vitro heatinduced protein denaturation assay was used for the anti-inflammatory effect of the tested compounds.
Both compounds evoked marked cytotoxic activity with IC of 47.40 and 36.91 ppm, respectively. In Epstein-Barr-Virus (EVA) early antigen activation assay compounds 1 and 2 showed IC50 values of 426 ppm and 412 ppm, respectively. The tested compounds showed 60% survival rate of the lymphoblastoid Raji cells at a concentration of 1000 (mol / ratio 32 pmol TPA). In a two-stage carcinogenesis assay on mouse skin, both compounds significantly delayed the formation of papillomas on mouse skin. Compound 1 showed 50% effect at 14th week, whereas compound 2 exerted the same effect at 13th week, while both provoked 100% effect at 20th week. Both compounds significantly attenuated thermal-induced protein denaturation with EC50 values of 298 and 264 μg/mL, respectively. The dimeric napthoquiones were evaluated for their effects on the reversion of Multidrug-Resistant (MDR) cell lines mediated by P-glycoprotein using rhodamine 123 dye-based exclusion screening test on human mdr1 gene transfected thymic lymphoma L5178 cell line. The compounds 1 and 2 exhibited promising MDR reversal effect in a dose-dependent manner against mouse T-lymphoma cell line. Docking results also showed that both compounds have good docking statistics as compared with standard.
Both the compounds demonstrated marked anti-tumor, anti-carcinogenic, and MDR reversal effects with significant attenuation of thermal-induced denaturation of the protein. These compounds may explain the traditional uses of D. lotus which might be effective anticancer agents.
癌症是一种基因异质性的复杂疾病，现有疗法效果不佳，是全球主要的死亡原因。发现疗效更高、副作用更小的新型抗癌药物对医疗专业人员来说是一项巨大挑战。
本研究聚焦于从君迁子根部分离得到的两种已知二聚萘醌——柿皮素（1）和8-羟基柿皮素（2）的抗癌潜力。
采用体外爱泼斯坦-巴尔病毒（EBV）早期抗原激活试验评估受试化合物的抗肿瘤潜力，随后在小鼠皮肤上进行两阶段致癌试验以评估其抗癌效果。还评估了化合物的多药耐药逆转潜力。采用体外热诱导蛋白变性试验评估受试化合物的抗炎作用。
两种化合物均具有显著的细胞毒性活性，IC50分别为47.40和36.91 ppm。在爱泼斯坦-巴尔病毒（EBV）早期抗原激活试验中，化合物1和2的IC50值分别为426 ppm和412 ppm。在浓度为1000（mol / 比例32 pmol TPA）时，受试化合物使淋巴母细胞样Raji细胞的存活率达到60%。在小鼠皮肤两阶段致癌试验中，两种化合物均显著延迟了小鼠皮肤上乳头状瘤的形成。化合物1在第14周时显示出50%的效果，而化合物2在第13周时产生相同效果，两者在第20周时均产生100%的效果。两种化合物均显著减弱热诱导的蛋白变性，EC50值分别为298和264 μg/mL。使用基于罗丹明123染料的排除筛选试验，在人mdr1基因转染的胸腺淋巴瘤L5178细胞系上评估二聚萘醌对P-糖蛋白介导的多药耐药（MDR）细胞系逆转的影响。化合物1和2对小鼠T淋巴瘤细胞系呈现出有前景且剂量依赖性的MDR逆转作用。对接结果还表明，与标准物相比，两种化合物均具有良好的对接统计结果。
两种化合物均表现出显著的抗肿瘤、抗癌和MDR逆转作用，并能显著减弱热诱导的蛋白变性。这些化合物可能解释了君迁子的传统用途，其可能是有效的抗癌药物。
