Division of Molecular Medicine, Bose Institute, Kolkata 700054, India.
Division of Molecular Medicine, Bose Institute, Kolkata 700054, India.
Int Immunopharmacol. 2020 Nov;88:106932. doi: 10.1016/j.intimp.2020.106932. Epub 2020 Sep 2.
Melanoma is one of the most aggressive malignancies and its treatment remains challenging due to its highly metastatic property and availability of limited effective drugs. In addition, immunosuppresive tumor microenvironment (TME) has been identified as major barrier to evoke anti-tumor response in melanoma. Recent studies revealed that immunosuppressive TME is directly correlated with heightened activations of T regulatory cells (Tregs) and Myeloid derived suppressor cells (MDSCs) functions. In this study, we investigated the anti-cancer effect of a triterpenoid, glycyrrhizic acid (GA) on melanoma. Our study revealed that GA not only exhibited anti-proliferative effects on melanoma cells it significantly restricted progression of melanoma tumor. However, the therapeutic efficacy of GA in impressive regression of tumor was found to be directly correlated with induction of apoptosis and modulation of cytokines from Th2 to Th1 type. To unravel the mechanism of anti-melanoma effect of GA, it has been delineated that GA inhibits pSTAT3 to evade anti-tumor suppressive function of Tregs and MDSCs. Downregulation of FOXP3, GITR and CTLA4 in tumor-infiltrating Tregs and inhibition of Cox2, PGE2 and Arginase 1 in intra-tumoral MDSC were evidenced as some of the key events during therapeutic intervention of GA in melanoma management. Moreover, GA effectively restricted advanced stage solid tumor while used in combination with Mycobacterium indicus pranii, a known immunomodulator, which alone is reported to be ineffective to restrict advanced stage solid tumor. Thus, our findings may open up a novel insight of GA as a promising agent in cancer immunotherapy or adjuvant therapy in future.
黑色素瘤是最具侵袭性的恶性肿瘤之一，由于其高度转移性和有限有效药物的可用性，其治疗仍然具有挑战性。此外，免疫抑制性肿瘤微环境（TME）已被确定为在黑色素瘤中引发抗肿瘤反应的主要障碍。最近的研究表明，免疫抑制性 TME 与 T 调节细胞（Tregs）和髓源抑制细胞（MDSCs）功能的高度激活直接相关。在这项研究中，我们研究了三萜酸甘草酸（GA）对黑色素瘤的抗癌作用。我们的研究表明，GA 不仅对黑色素瘤细胞表现出抗增殖作用，而且显著限制了黑色素瘤肿瘤的进展。然而，GA 在肿瘤令人印象深刻的消退中的治疗效果被发现与诱导细胞凋亡和将细胞因子从 Th2 型调节为 Th1 型直接相关。为了阐明 GA 抗黑色素瘤作用的机制，已经阐明 GA 抑制 pSTAT3 以逃避 Tregs 和 MDSCs 的抗肿瘤抑制功能。肿瘤浸润性 Tregs 中 FOXP3、GITR 和 CTLA4 的下调以及肿瘤内 MDSC 中 Cox2、PGE2 和精氨酸酶 1 的抑制被证明是 GA 在黑色素瘤管理中的治疗干预的一些关键事件。此外，GA 在与已知免疫调节剂印度分枝杆菌（Mycobacterium indicus pranii）联合使用时有效地限制了晚期实体瘤，而单独使用时据报道无法限制晚期实体瘤。因此，我们的发现可能为 GA 作为未来癌症免疫治疗或辅助治疗中的一种有前途的药物提供新的见解。
