Anti-cancer effect of marchantin C via inducing lung cancer cellular senescence associated with less secretory phenotype

• Published in: Biochimica et biophysica acta. General subjects Vol. 1863; no. 10; pp. 1443 - 1457
• Main Authors: Zhang, Xiu-Lei, Ji, Xiao-Tian, Sun, Bin, Qian, Li-Lin, Hu, Xue-Lei, Lou, Hong-Xiang, Yuan, Hui-Qing
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.10.2019
• Subjects: Animals; Antineoplastic Agents - pharmacology; Bibenzyls - pharmacology; Cell Line, Tumor; Cellular Senescence - drug effects; DNA Damage; DNA Repair - genetics; Female; Humans; Lung Neoplasms - metabolism; Lung Neoplasms - pathology; Marchantin C; Mice; Mice, Inbred BALB C; Mice, Nude; Phenyl Ethers - pharmacology; Proto-Oncogene Proteins p21(ras) - metabolism; Reactive Oxygen Species - metabolism; SASP; Senescence; Toxicity; Xenograft Model Antitumor Assays; Senescence; Toxicity; Marchantin C; SASP; DNA damage
• ISSN: 0304-4165; 1872-8006
• DOI: 10.1016/j.bbagen.2019.05.006

Lung cancer is the leading cause of global cancer deaths. Current chemotherapeutic agents for lung cancer treatment are generally accompanied with severe side effects. Here, we report that marchantin C (Mar-C), a potential natural compound with little chemotherapeutic toxicity, exerts a well anti-tumor effect against lung cancer via inducing cellular senescence. The antitumor activity of Mar-C was evaluated by MTT and colony formation in vitro cytotoxicity assays, and xenograft and homograft in vivo model. Antitumor mechanisms of Mar-C were investigated through SA-β-gal staining, Q-PCR, immunoblotting, immunofluorescence, protein array and siRNA knocking-down analysis. Mar-C selectively induces senescence of lung cancer cells with limited cytotoxicity on normal or non-neoplastic cells. Mar-C-induced senescence was associated with the elevation of ROS and activation of DNA-damage, and largely dependent of prolonged p21CIP1 accumulation. The senescence-associated secretory phenotype (SASP) induced by Mar-C was distinct from doxorubicin-induced. Furthermore, Mar-C exhibited an inhibitory activity on tumor growth with little toxicity in animal studies, and significantly prolonged the survival time of tumor-bearing mice than that of doxorubicin or vehicle treatments. Mar-C selectively inhibited tumor growth via the induction of cancer cell senescence and had little chemotherapeutic toxicity, suggesting the potential of Mar-C as a promising anticancer agent. This study provided evidence to identify a novelty of Mar-C that exerted antitumor activity on lung cancer through induction of senescence with limited toxicity. [Display omitted] •Mar-C selectively inhibits proliferation of lung cancer cells through inducing cellular senescence.•Mar-C induces p21-dependent cellular senescence via the accumulation of DNA damage.•Mar-C triggers DNA damage by the ROS production and DNA repair genes repression.•Mar-C exerts a distinct senescence-associated secretory phenotype on cancer cells.•Mar-C is an ideal anti-tumor agent with little chemotherapy toxicity in vivo.