Inactivation of TFEB and NF-κB by marchantin M alleviates the chemotherapy-driven pro-tumorigenic senescent secretion.
Acta Pharm Sin B
; 9(5): 923-936, 2019 Sep.
Article
in En
| MEDLINE
| ID: mdl-31649843
ABSTRACT
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-κB (NF-κB) 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.
ALT, glutamic-pyruvic transaminase; AST, transaminase; BUN, blood urea nitrogen; CDDP, cisplatin; CI, combinatory index; CM, conditioned media; CREA, creatinine; CT-like, both chymotrypsin-like; DMSO, dimethyl sulfoxide; Doc, docetaxel; Doxo, doxorubicin; Drug resistance; EdU, 5-ethynyl-2'-deoxyuridine; LPS, lipopolysaccharide; MTT, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide; Mar-M, Marchantin M; Marchantin M; NF-κB; NF-κB, nuclear factor-κB; PGPH, peptidylglutamyl hydrolyzing; PI, propidium iodide; ROS, reactive oxygen species; SA-ß-gal, senescence-associated ß-galactosidase; SASP; SASP, senescence-associated secretory phenotype; Sv, starvation; TCGA, the Cancer Genome Atlas; TFEB; TFEB, transcription factor EB; Tg, thapsigargin
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Type of study:
Prognostic_studies
Language:
En
Journal:
Acta Pharm Sin B
Year:
2019
Document type:
Article
Affiliation country:
China