br Conclusion br Anti cancer
Anti-cancer drug discovery and development are considered as the grand challenges for the pharmaceutical industry. Extremely dynamic mitotic-spindle microtubules indeed remain the most successful and promising targets for anti-cancer therapy. Microtubule-stabilizing agents are continually playing an important role in anti-cancer drug discovery and development. In this study, we have shown that ITH-6 is an eﬀective cytotoxic agent against colon cancer cells and exhibits a better cytotoxic eﬀect compared to other drugs approved for colon cancer. Mechanistically, ITH-6 inhibits tubulin polymerization, alters the Pertussis Toxin progression and induces apoptosis by elevating the intra
S. Narayanan, et al.
cellular ROS and decreasing the intracellular GSH levels. Together with its mechanism of action, ITH-6 could be a potential anti-cancer drug candidate for colorectal cancer treatment.
S.N. and Z.-S.C. designed the experiments and U.N. and M.A. syn-thesized the compound. S.N., P.G. and N.K. performed the experiments, S.N. and P.G. analyzed the data, S.N., Z.-S.C. and M.A. wrote the manuscript. All authors read and approved the final manuscript.
This work was partially supported by St. John's University Research Seed Grant (No. 579-1110-7002), Department of Pharmaceutical Sciences at St. John's University to Dr. Z.S. Chen.
Conflict of interest
The authors declare no potential conflicts of interest.
The authors are thankful to Dr. Susan E. Bates (Columbia University, NY) for providing SW620 cell lines and Dr. Suresh Ambudkar (NIH, MD) for providing HEK293 cell line.
Appendix A. Supplementary data
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Anti-cancer effect of marchantin C via inducing lung cancer cellular senescence associated with less secretory phenotype
Xiu-Lei Zhanga,b,1, Xiao-Tian Jia,b, Bin Sunc, Li-Lin Qianb, Xue-Lei Hud, Hong-Xiang Louc, Hui-Qing Yuana,b, a Institute of Medical Sciences, The Second Hospital of Shandong University, Jinan, China b Department of Biochemistry and Molecular Biology, School of Medicine, Shandong University, Jinan, China c Key Laboratory of Natural Products & Chemical Biology, Ministry of Education, Department of Natural Products Chemistry, National Glycoengineering Research Center, School of Pharmaceutical Sciences, Shandong University, Jinan, China d Department of thoracic surgery, Qilu Hospital of Shandong University, Jinan, China
Background: 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.
Methods: 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.
Results: 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 phe-notype (SASP) induced by Mar-C was distinct from doxorubicin-induced. Furthermore, Mar-C exhibited an in-hibitory 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.