摘要
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 proinflammatory 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-k B(NF-k 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.
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 proinflammatory 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-k B(NF-k 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.
基金
supported by the National Natural Science Foundation of China(81473238,81872896,and 81874293)
the Shandong Key Innovative Research Program(2018CXGC1216,China)
