Inactivation of TFEB and NF-B by marchantin M alleviates the chemotherapy-driven pro-tumorigenic senescent secretion.
10.1016/j.apsb.2019.08.007
- Author:
Huanmin NIU
1
;
Lilin QIAN
1
;
Bin SUN
2
;
Wenjian LIU
1
;
Fang WANG
1
;
Qian WANG
1
;
Xiaotian JI
1
;
Yanhai LUO
1
;
Effat Un NESA
3
;
Hongxiang LOU
2
;
Huiqing YUAN
1
Author Information
1. Institute of Medical Sciences/Department of Biochemistry and Molecular Biology, the Second Hospital of Shandong University, Jinan 250033, China.
2. Key Laboratory of Natural Products & Chemical Biology, Ministry of Education, Department of Natural Products Chemistry, School of Pharmaceutical Sciences, Shandong University, Jinan 250012, China.
3. Department of Radiation Oncology, Qilu Hospital of Shandong University, Jinan 250012, China.
- Publication Type:Journal Article
- Keywords:
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-β-gal, senescence-associated β-galactosidase;
SASP;
SASP, senescence-associated secretory phenotype;
Sv, starvation;
TCGA, the Cancer Genome Atlas;
TFEB;
TFEB, transcription factor EB;
Tg, thapsigargin
- From:
Acta Pharmaceutica Sinica B
2019;9(5):923-936
- CountryChina
- Language:English
-
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-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.
