Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD 21287, USA.
Int J Mol Sci. 2022 Jul 22;23(15):8083. doi: 10.3390/ijms23158083.
Hepatocellular carcinoma (HCC) incidence, as well as related mortality, has been steadily increasing in the USA and across the globe, partly due to the lack of effective therapeutic options for advanced HCC. Though sorafenib is considered standard-of-care for advanced HCC, it only improves median survival by a few months when compared to placebo. Sorafenib is also associated with several unpleasant side effects that often lead to early abatement of therapy. Here, we investigate whether a combination regimen including low-dose sorafenib and a non-toxic dose of anti-diabetic drug metformin can achieve effective inhibition of HCC. Indeed, combining metformin with low-dose sorafenib inhibited growth, proliferation, migration, and invasion potential of HCC cells. We observed a 5.3- and 1.9-fold increase in sub-G1 population in the combination treatment compared to sorafenib alone. We found that the combination of metformin enhanced the efficacy of sorafenib and inhibited the MAPK/ERK/Stat3 axis. Our in vivo studies corroborated the in vitro findings, and mice harboring HepG2-derived tumors showed effective tumor reduction upon treatment with low-dose sorafenib and metformin combination. This work sheds light on a therapeutic strategy aiming to augment sorafenib efficacy or dose-de-escalation that may prove beneficial in circumventing sorafenib resistance as well as minimizing related side effects.
肝细胞癌 (HCC) 的发病率以及相关死亡率在美国和全球范围内一直在稳步上升，部分原因是缺乏有效的晚期 HCC 治疗选择。索拉非尼虽然被认为是晚期 HCC 的标准治疗方法，但与安慰剂相比，仅能将中位生存期延长几个月。索拉非尼还与几种令人不快的副作用相关，这些副作用常常导致治疗提前中断。在这里，我们研究了包括低剂量索拉非尼和非毒性剂量抗糖尿病药物二甲双胍的联合治疗方案是否可以有效抑制 HCC。事实上，二甲双胍与低剂量索拉非尼联合使用可抑制 HCC 细胞的生长、增殖、迁移和侵袭能力。与单独使用索拉非尼相比，联合治疗组中 sub-G1 群体增加了 5.3 倍和 1.9 倍。我们发现，二甲双胍增强了索拉非尼的疗效并抑制了 MAPK/ERK/Stat3 通路。我们的体内研究证实了体外研究结果，并且携带 HepG2 衍生肿瘤的小鼠在接受低剂量索拉非尼和二甲双胍联合治疗后显示出有效的肿瘤缩小。这项工作为增强索拉非尼疗效或降低剂量的治疗策略提供了启示，这可能有助于避免索拉非尼耐药并最大程度减少相关副作用。
