PPMP, a novel tubulin-depolymerizing agent against esophageal cancer in patient-derived tumor xenografts.

Abstract

Esophageal cancer is one of the least studied and deadliest cancers worldwide with a poor prognosis due to limited options for treatment. Chemotherapy agents such as the microtubule-targeting compounds are the mainstay of palliation for advanced esophageal cancer treatment. However, the toxicity and side effects of tubulin-binding agents (TBAs) have promoted the development of novel, more potent but less toxic TBAs. Herein, we identified 2-[4-(3,4-dimethoxyphenyl)-3-methyl-1H-pyrazol-5-yl]-5-[(2-methylprop-2-en-1-yl)oxy] phenol (PPMP) as a novel TBA for esophageal cancer treatment. PPMP markedly inhibited tubulin polymerization, and decreased viability and anchorage-independent growth of esophageal cancer cell lines, effects that were accompanied by G2/M arrest and apoptosis. Importantly, we produced patient-derived esophageal cancer xenografts to evaluate the therapeutic effect of PPMP in a setting that best mimics the clinical context in patients with esophageal cancer. Overall, we identified PPMP as a novel microtubule-destabilizing compound and as a new therapeutic agent against esophageal carcinoma.

• Authors: Yuqiao Sheng, Kangdong Liu, Qiong Wu, Naomi Oi, Hanyong Chen, Kanamata Reddy, Yanan Jiang, Ke Yao, Haitao Li, Wei Li, Yi Zhang, Mohammad Saleem, Wei-Ya Ma, Ann M Bode, Ziming Dong, Zigang Dong
• Journal: Oncotarget (Oncotarget) Vol. 7 Issue 21 Pg. 30977-89 (May 24 2016) ISSN: 1949-2553 [Electronic] United States
• PMID: 27129160 (Publication Type: Journal Article)

Chemical References

• Tubulin
• Tubulin Modulators
• 4-propionyloxy-4-phenyl-N-methylpiperidine
• Meperidine

Topics

• Animals
• Apoptosis (drug effects)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Cell Survival (drug effects)
• Esophageal Neoplasms (drug therapy, metabolism, pathology)
• G2 Phase Cell Cycle Checkpoints (drug effects)
• Humans
• M Phase Cell Cycle Checkpoints (drug effects)
• Male
• Meperidine (analogs & derivatives, pharmacology)
• Mice
• Middle Aged
• Models, Molecular
• Tubulin (metabolism)
• Tubulin Modulators (pharmacology)
• Xenograft Model Antitumor Assays