1.Inactivation of TFEB and NF-B by marchantin M alleviates the chemotherapy-driven pro-tumorigenic senescent secretion.
Huanmin NIU ; Lilin QIAN ; Bin SUN ; Wenjian LIU ; Fang WANG ; Qian WANG ; Xiaotian JI ; Yanhai LUO ; Effat Un NESA ; Hongxiang LOU ; Huiqing YUAN
Acta Pharmaceutica Sinica B 2019;9(5):923-936
It is critical to regulate the senescence-associated secretory phenotype (SASP) due to its effect on promoting malignant phenotypes and limiting the efficiency of cancer therapy. In this study, we demonstrated that marchantin M (Mar-M, a naturally occurring bisbibenzyl) suppressed pro-inflammatory SASP components which were elevated in chemotherapy-resistant cells. Mar-M treatment attenuated the pro-tumorigenic effects of SASP and enhanced survival in drug-resistant mouse models. No toxicity was detected on normal fibroblast cells or in animals following this treatment. Inactivation of transcription factor EB (TFEB) and nuclear factor-B (NF-B) by Mar-M significantly accounted for its suppression on the components of SASP. Furthermore, inhibition of SASP by Mar-M contributed to a synergistic effect during co-treatment with doxorubicin to lower toxicity and enhance antitumor efficacy. Thus, chemotherapy-driven pro-inflammatory activity, seen to contribute to drug-resistance, is an important target for Mar-M. By decreasing SASP, Mar-M may be a potential approach to overcome tumor malignancy.
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