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

• Published in: Cancer science Vol. 111; no. 12; pp. 4336 - 4347
• Main Authors: Zhong, Cheng, Kayamori, Kensuke, Koide, Shuhei, Shinoda, Daisuke, Oshima, Motohiko, Nakajima‐Takagi, Yaeko, Nagai, Yurie, Mimura, Naoya, Sakaida, Emiko, Yamazaki, Satoshi, Iwano, Satoshi, Miyawaki, Atsushi, Ito, Ryoji, Tohyama, Kaoru, Yamaguchi, Kiyoshi, Furukawa, Yoichi, Lennox, William, Sheedy, Josephine, Weetall, Marla, Iwama, Atsushi
• Format: Journal Article
• Language: English
• Published: England John Wiley & Sons, Inc 01.12.2020; John Wiley and Sons Inc
• Subjects: 5-aza-2'-deoxycytidine; Acute myeloid leukemia; Animal models; Animals; Antimetabolites, Antineoplastic - pharmacology; Antineoplastic drugs; Antitumor agents; Apoptosis; Apoptosis - drug effects; Apoptosis - genetics; Benzimidazoles - pharmacology; Benzimidazoles - therapeutic use; Binding sites; Bioluminescence; Blood; Cancer; Care and treatment; Cell cycle; Cell death; Cell division; Cell Line, Tumor; Cell proliferation; Cell Proliferation - drug effects; chemotherapy; Cytotoxicity; Decitabine - pharmacology; Deoxyribonucleic acid; Depolymerization; DNA; DNA hypomethylating agents; DNA methylation; FDA approval; G2 Phase - drug effects; Gene expression; Genomes; Hematology; Heterografts; HL-60 Cells; Humans; Laboratory animals; Leukemia; Mice; Microtubules; Mitosis; Myelodysplastic syndrome; Myelodysplastic Syndromes - drug therapy; Myelodysplastic Syndromes - genetics; Myeloid leukemia; Original; Ovarian cancer; p53 Protein; Paclitaxel - pharmacology; Polymerization; Pyrazines - pharmacology; Pyrazines - therapeutic use; Sequence Analysis, RNA - methods; Software; Solid tumors; Tubulin; Tubulin - drug effects; Tubulin Modulators - pharmacology; Tubulin Modulators - therapeutic use; Tubulin polymerization inhibitor; Tubulins; Tumor proteins; Vincristine; Vincristine - pharmacology; Xenografts; Japan; Tubulin polymerization inhibitor; chemotherapy; DNA hypomethylating agents; Myelodysplastic syndrome
• ISSN: 1347-9032; 1349-7006
• DOI: 10.1111/cas.14684

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. PTC‐028, a novel microtubule polymerization inhibitor, suppresses the growth of MDS cells. PTC‐028 synergizes with DNA hypomethylating agents to inhibit the growth of MDS cells. PTC‐028 prolongs the survival of mice in a xenograft MDS model.