title: The novel tubulin polymerization inhibitor MHPT exhibits selective anti-tumor activity against rhabdomyosarcoma in vitro and in vivo.
abstract: The dose-limiting toxicity caused by standard chemotherapy has become a major roadblock to successful rhabdomyosarcoma chemotherapy. By screening a thiazolidinone library including 372 compounds, a novel synthetic compound, 2-((4-hydroxyphenyl)imino)-5-(3-methoxybenzylidene)thiazolidin-4-one (MHPT), was identified as a potent and selective anti-rhabdomyosarcoma agent. MHPT inhibited 50% of the growth of the rhabdomyosarcoma cell lines RD and SJ-RH30 at 0.44 μM and 1.35 μM, respectively, while displaying no obvious toxicity against normal human fibroblast cells at 100 μM. Further investigation revealed that MHPT suppressed the polymerization of tubulin, leading to rhabdomyosarcoma cell growth arrest at the G2/M phase followed by apoptosis. In vivo, MHPT inhibited tumor growth by 48.6% relative to the vehicle control after 5 intraperitoneal injections of 40 mg/kg without appreciable toxicity to normal tissues and systems in an RD xenograft mouse model, while vincristine caused lethal toxicity when similar growth inhibition was achieved. As a moderate tubulin polymerization inhibitor compared with vincristine, MHPT requires a more dynamic tubulin to exert its cytotoxicity, which is a situation that only exists in cancer cells. This attribute may account for the low toxicity of MHPT in normal cells. Our data suggest that MHPT has the potential to be further developed into a selective anti-rhabdomyosarcoma drug with low toxicity.
authors: School of Chemistry and Chemical Engineering, Shandong University, Shandong Province, Jinan, China.
authors: Yan
authors: Y
authors: Mu
authors: School of Chemistry and Chemical Engineering, Shandong University, Shandong Province, Jinan, China.
authors: Yin
authors: Y
authors: Liu
authors: School of Chemistry and Chemical Engineering, Shandong University, Shandong Province, Jinan, China.
authors: Liwen
authors: L
authors: Li
authors: School of Chemistry and Chemical Engineering, Shandong University, Shandong Province, Jinan, China.
authors: Cong
authors: C
authors: Tian
authors: School of Chemistry and Chemical Engineering, Shandong University, Shandong Province, Jinan, China.
authors: Hongyu
authors: H
authors: Zhou
authors: School of Chemistry and Chemical Engineering, Shandong University, Shandong Province, Jinan, China.
authors: Qiu
authors: Q
authors: Zhang
authors: School of Chemistry and Chemical Engineering, Shandong University, Shandong Province, Jinan, China.
authors: Bing
authors: B
authors: Yan
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D051379:Mice; D055503:Protein Multimerization / Q000187:drug effects*; D012208:Rhabdomyosarcoma / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D014404:Tubulin / Q000737:chemistry / Q000378:metabolism*; D050257:Tubulin Modulators / Q000008:administration & dosage / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D014404:Tubulin; D050257:Tubulin Modulators