Efficacy of the novel tubulin polymerization inhibitor PTC-028 for myelodysplastic syndrome.

Abstract

Monomer tubulin polymerize into microtubules, which are highly dynamic and play a critical role in mitosis. Therefore, microtubule dynamics are an important target for anticancer drugs. The inhibition of tubulin polymerization or depolymerization was previously targeted and exhibited efficacy against solid tumors. The novel small molecule PTC596 directly binds tubulin, inhibits microtubule polymerization, downregulates MCL-1, and induces p53-independent apoptosis in acute myeloid leukemia cells. We herein investigated the efficacy of PTC-028, a structural analog of PTC596, for myelodysplastic syndrome (MDS). PTC-028 suppressed growth and induced apoptosis in MDS cell lines. The efficacy of PTC028 in primary MDS samples was confirmed using cell proliferation assays. PTC-028 synergized with hypomethylating agents, such as decitabine and azacitidine, to inhibit growth and induce apoptosis in MDS cells. Mechanistically, a treatment with PTC-028 induced G2/M arrest followed by apoptotic cell death. We also assessed the efficacy of PTC-028 in a xenograft mouse model of MDS using the MDS cell line, MDS-L, and the AkaBLI bioluminescence imaging system, which is composed of AkaLumine-HCl and Akaluc. PTC-028 prolonged the survival of mice in xenograft models. The present results suggest a chemotherapeutic strategy for MDS through the disruption of microtubule dynamics in combination with DNA hypomethylating agents.

• Authors: Cheng Zhong, Kensuke Kayamori, Shuhei Koide, Daisuke Shinoda, Motohiko Oshima, Yaeko Nakajima-Takagi, Yurie Nagai, Naoya Mimura, Emiko Sakaida, Satoshi Yamazaki, Satoshi Iwano, Atsushi Miyawaki, Ryoji Ito, Kaoru Tohyama, Kiyoshi Yamaguchi, Yoichi Furukawa, William Lennox, Josephine Sheedy, Marla Weetall, Atsushi Iwama
• Journal: Cancer science (Cancer Sci) Vol. 111 Issue 12 Pg. 4336-4347 (Dec 2020) ISSN: 1349-7006 [Electronic] England
• PMID: 33037737 (Publication Type: Journal Article)
• Copyright: © 2020 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.

Chemical References

• Antimetabolites, Antineoplastic
• Benzimidazoles
• PTC-028
• PTC596
• Pyrazines
• Tubulin
• Tubulin Modulators
• Vincristine
• Decitabine
• Paclitaxel

Topics

• Animals
• Antimetabolites, Antineoplastic (pharmacology)
• Apoptosis (drug effects, genetics)
• Benzimidazoles (pharmacology, therapeutic use)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Decitabine (pharmacology)
• G2 Phase (drug effects)
• HL-60 Cells
• Heterografts
• Humans
• Mice
• Myelodysplastic Syndromes (drug therapy, genetics)
• Paclitaxel (pharmacology)
• Pyrazines (pharmacology, therapeutic use)
• Sequence Analysis, RNA (methods)
• Tubulin (drug effects)
• Tubulin Modulators (pharmacology, therapeutic use)
• Vincristine (pharmacology)