Tian Shiliu, Su Rui, Wu Ke, Zhou Xuhan, Vadgama Jaydutt V, Wu Yong
Key Laboratory of Exercise and Health Sciences of Ministry of Education, Shanghai University of Sport, Shanghai 200438, China.
Fujian Sports Vocational Education and Technical College, Fuzhou 350001, China.
J Pers Med. 2022 Aug 16;12(8):1318. doi: 10.3390/jpm12081318.
Recent studies have shown that diaporine, a novel fungal metabolic product, has a strong in vitro and in vivo anticancer effect on human non-small-cell lung and breast cancers. In this study, three human hepatocarcinoma cell lines (HepG2, Hep3B, and Huh7) were used to evaluate the efficacy of diaporine alone and in combination with the standard cytotoxic drugs oxaliplatin and doxorubicin for the treatment of liver cancer. We demonstrated that diaporine, oxaliplatin, and doxorubicin triggered a concentration- and time-dependent decrease in the number of HepG2 cells. Diaporine at a concentration of 2.5 μM showed almost 100% inhibition of cell counts at 72 h. Similar effects were observed only with much higher concentrations (100 μM) of oxaliplatin or doxorubicin. Decreases in cell numbers after 48 h treatment with diaporine, oxaliplatin, and doxorubicin were also demonstrated in two additional hepatoma cell lines, Hep3B and Huh7. The combination of these drugs at low concentration for 48 h in vitro noticeably showed that diaporine improved the inhibitory effect on the number of cancer cells induced by oxaliplatin or doxorubicin. Additionally, this combination effectively inhibited colony growth in vitro. We found that inhibition of phosphorylation of ERK1/2 significantly increased when diaporine was used in combination with other agents. In addition, we also found that when diaporine was used in combination with doxorubicin or oxaliplatin, their proapoptotic effect greatly increased. We further revealed that the induction of apoptosis in hepatoma cells after treatment is due, at least in part, to the inhibition of phosphorylation of AKT, leading to the activation of caspase-3, inactivation of poly (ADP-ribose) polymerase (PARP), and subsequently to DNA damage, as indicated by the increased level of H2AX. Based on these findings, we suggest that diaporine in combination with the standard cytotoxic drugs oxaliplatin and doxorubicin may play a role in the treatment of liver cancer.
最近的研究表明，新型真菌代谢产物二孢菌素对人类非小细胞肺癌和乳腺癌具有强大的体外和体内抗癌作用。在本研究中，使用三种人类肝癌细胞系（HepG2、Hep3B和Huh7）来评估二孢菌素单独使用以及与标准细胞毒性药物奥沙利铂和阿霉素联合使用治疗肝癌的疗效。我们证明，二孢菌素、奥沙利铂和阿霉素可导致HepG2细胞数量呈浓度和时间依赖性减少。浓度为2.5μM的二孢菌素在72小时时对细胞计数的抑制率几乎达到100%。仅在更高浓度（100μM）的奥沙利铂或阿霉素下才观察到类似效果。在另外两种肝癌细胞系Hep3B和Huh7中，用二孢菌素、奥沙利铂和阿霉素处理48小时后，细胞数量也出现减少。在体外将这些药物低浓度联合使用48小时，结果显著表明，二孢菌素增强了奥沙利铂或阿霉素对癌细胞数量的抑制作用。此外，这种联合用药在体外有效抑制了集落生长。我们发现，二孢菌素与其他药物联合使用时，ERK1/2磷酸化的抑制作用显著增强。此外，我们还发现，二孢菌素与阿霉素或奥沙利铂联合使用时，它们的促凋亡作用大大增强。我们进一步揭示，治疗后肝癌细胞凋亡的诱导至少部分归因于AKT磷酸化的抑制，从而导致caspase-3激活、聚（ADP-核糖）聚合酶（PARP）失活，随后导致DNA损伤，H2AX水平升高即表明了这一点。基于这些发现，我们认为二孢菌素与标准细胞毒性药物奥沙利铂和阿霉素联合使用可能在肝癌治疗中发挥作用。
