YSL-12, a novel microtubule-destabilizing agent, exerts potent anti-tumor activity against colon cancer in vitro and in vivo.
Microtubules play a central role in various fundamental cell functions and thus become an attractive target for cancer therapy. A novel compound YSL-12 is a combretastatin A-4 (CA-4) analogue with more stability. We investigated its anti-tumor activity and mechanisms in vitro and in vivo for the first time.



Cytotoxicity was evaluated by MTT method. In vitro microtubule polymerization assay was performed using a fluorescence-based method by multifunction fluorescence microplate reader. Intracellular microtubule network was detected by immunofluorescence method. Cell cycle analysis and apoptosis were measured by flow cytometry. Metabolic stability was recorded by liquid chromatography-ultraviolet detection and liquid chromatography-mass spectrometry. In vivo anti-tumor activity was assessed using HT-29 colon carcinoma xenografts established in BALB/c nude mice.



YSL-12 displayed nanomolar-level cytotoxicity against various human cancer cell lines. A high selectivity toward normal cells and potent activity toward drug-resistant cells were also observed. YSL-12 was identified as tubulin polymerization inhibitor evidenced by effectively inhibits tubulin polymerization and heavily disrupted microtubule networks in living HT-29 cells. YSL-12 displayed potent disruption effect of pre-established tumor vasculature in vitro. In addition, YSL-12 treatment also caused cell cycle arrest in the G2/M phase and induced cell apoptosis in a dose-dependent manner. In vitro metabolic stability study revealed YSL-12 displayed considerable better stability than CA-4 in liver microsomes. In vivo, YSL-12 delayed tumor growth with 69.4 % growth inhibition.



YSL-12 is a promising microtubule inhibitor that has great potential for the treatment of colon carcinoma in vitro and in vivo and worth being a candidate for further development of cancer therapy.
Department of Pharmacy, Affiliated Hospital of Guangdong Medical University, Zhanjiang, China. decai_gmu@163.com.
De
D
Cai
Department of Pharmacy, Affiliated Hospital of Guangdong Medical University, Zhanjiang, China.
Zhiqing
Z
Qiu
Department of Respiratory Medical, Affiliated Hospital of Guangdong Medical University, Zhanjiang, China.
Weimin
W
Yao
College of Pharmacy, Guangdong Medical University, Zhanjiang, China.
Yuyu
Y
Liu
Department of Obstetrics and Gynecology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, China.
Haixiang
H
Huang
Department of Oncology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, China.
Sihai
S
Liao
Department of Pharmacy, Central People's Hospital of Zhanjiang, Zhanjiang, China.
Qun
Q
Luo
Department of Pharmacy, Affiliated Hospital of Guangdong Medical University, Zhanjiang, China.
Liming
L
Xie
Department of Pharmacy, Affiliated Hospital of Guangdong Medical University, Zhanjiang, China.
Zhixiu
Z
Lin
D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects*; D001549:Benzamides / Q000009:adverse effects / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007546:Isoquinolines / Q000009:adverse effects / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D051379:Mice; D008819:Mice, Nude; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D008870:Microtubules / Q000187:drug effects*; D015394:Molecular Structure; D051381:Rats; D050257:Tubulin Modulators / Q000009:adverse effects / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D001549:Benzamides; D007546:Isoquinolines; D050257:Tubulin Modulators; C000613984:YSL-12
Apoptosis; Cell cycle; Cytotoxicity; In vivo anti-tumor activity; Metabolic stability; Microtubules