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The combination of the tubulin binding small molecule PTC596 and proteasome inhibitors suppresses the growth of myeloma cells
The novel small molecule PTC596 inhibits microtubule polymerization and its clinical development has been initiated for some solid cancers. We herein investigated the preclinical efficacy of PTC596 alone and in combination with proteasome inhibitors in the treatment of multiple myeloma (MM). PTC596...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Nature Publishing Group UK
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7822878/ https://www.ncbi.nlm.nih.gov/pubmed/33483574 http://dx.doi.org/10.1038/s41598-021-81577-x |
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author | Nagai, Yurie Mimura, Naoya Rizq, Ola Isshiki, Yusuke Oshima, Motohiko Rizk, Mohamed Saraya, Atsunori Koide, Shuhei Nakajima-Takagi, Yaeko Miyota, Makiko Chiba, Tetsuhiro Oshima-Hasegawa, Nagisa Muto, Tomoya Tsukamoto, Shokichi Mitsukawa, Shio Takeda, Yusuke Ohwada, Chikako Takeuchi, Masahiro Iseki, Tohru Nakaseko, Chiaki Lennox, William Sheedy, Josephine Weetall, Marla Yokote, Koutaro Iwama, Atsushi Sakaida, Emiko |
author_facet | Nagai, Yurie Mimura, Naoya Rizq, Ola Isshiki, Yusuke Oshima, Motohiko Rizk, Mohamed Saraya, Atsunori Koide, Shuhei Nakajima-Takagi, Yaeko Miyota, Makiko Chiba, Tetsuhiro Oshima-Hasegawa, Nagisa Muto, Tomoya Tsukamoto, Shokichi Mitsukawa, Shio Takeda, Yusuke Ohwada, Chikako Takeuchi, Masahiro Iseki, Tohru Nakaseko, Chiaki Lennox, William Sheedy, Josephine Weetall, Marla Yokote, Koutaro Iwama, Atsushi Sakaida, Emiko |
author_sort | Nagai, Yurie |
collection | PubMed |
description | The novel small molecule PTC596 inhibits microtubule polymerization and its clinical development has been initiated for some solid cancers. We herein investigated the preclinical efficacy of PTC596 alone and in combination with proteasome inhibitors in the treatment of multiple myeloma (MM). PTC596 inhibited the proliferation of MM cell lines as well as primary MM samples in vitro, and this was confirmed with MM cell lines in vivo. PTC596 synergized with bortezomib or carfilzomib to inhibit the growth of MM cells in vitro. The combination treatment of PTC596 with bortezomib exerted synergistic effects in a xenograft model of human MM cell lines in immunodeficient mice and exhibited acceptable tolerability. Mechanistically, treatment with PTC596 induced cell cycle arrest at G2/M phase followed by apoptotic cell death, associated with the inhibition of microtubule polymerization. RNA sequence analysis also revealed that PTC596 and the combination with bortezomib affected the cell cycle and apoptosis in MM cells. Importantly, endoplasmic reticulum stress induced by bortezomib was enhanced by PTC596, providing an underlying mechanism of action of the combination therapy. Our results indicate that PTC596 alone and in combination with proteasome inhibition are potential novel therapeutic options to improve outcomes in patients with MM. |
format | Online Article Text |
id | pubmed-7822878 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-78228782021-01-26 The combination of the tubulin binding small molecule PTC596 and proteasome inhibitors suppresses the growth of myeloma cells Nagai, Yurie Mimura, Naoya Rizq, Ola Isshiki, Yusuke Oshima, Motohiko Rizk, Mohamed Saraya, Atsunori Koide, Shuhei Nakajima-Takagi, Yaeko Miyota, Makiko Chiba, Tetsuhiro Oshima-Hasegawa, Nagisa Muto, Tomoya Tsukamoto, Shokichi Mitsukawa, Shio Takeda, Yusuke Ohwada, Chikako Takeuchi, Masahiro Iseki, Tohru Nakaseko, Chiaki Lennox, William Sheedy, Josephine Weetall, Marla Yokote, Koutaro Iwama, Atsushi Sakaida, Emiko Sci Rep Article The novel small molecule PTC596 inhibits microtubule polymerization and its clinical development has been initiated for some solid cancers. We herein investigated the preclinical efficacy of PTC596 alone and in combination with proteasome inhibitors in the treatment of multiple myeloma (MM). PTC596 inhibited the proliferation of MM cell lines as well as primary MM samples in vitro, and this was confirmed with MM cell lines in vivo. PTC596 synergized with bortezomib or carfilzomib to inhibit the growth of MM cells in vitro. The combination treatment of PTC596 with bortezomib exerted synergistic effects in a xenograft model of human MM cell lines in immunodeficient mice and exhibited acceptable tolerability. Mechanistically, treatment with PTC596 induced cell cycle arrest at G2/M phase followed by apoptotic cell death, associated with the inhibition of microtubule polymerization. RNA sequence analysis also revealed that PTC596 and the combination with bortezomib affected the cell cycle and apoptosis in MM cells. Importantly, endoplasmic reticulum stress induced by bortezomib was enhanced by PTC596, providing an underlying mechanism of action of the combination therapy. Our results indicate that PTC596 alone and in combination with proteasome inhibition are potential novel therapeutic options to improve outcomes in patients with MM. Nature Publishing Group UK 2021-01-22 /pmc/articles/PMC7822878/ /pubmed/33483574 http://dx.doi.org/10.1038/s41598-021-81577-x Text en © The Author(s) 2021 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. |
spellingShingle | Article Nagai, Yurie Mimura, Naoya Rizq, Ola Isshiki, Yusuke Oshima, Motohiko Rizk, Mohamed Saraya, Atsunori Koide, Shuhei Nakajima-Takagi, Yaeko Miyota, Makiko Chiba, Tetsuhiro Oshima-Hasegawa, Nagisa Muto, Tomoya Tsukamoto, Shokichi Mitsukawa, Shio Takeda, Yusuke Ohwada, Chikako Takeuchi, Masahiro Iseki, Tohru Nakaseko, Chiaki Lennox, William Sheedy, Josephine Weetall, Marla Yokote, Koutaro Iwama, Atsushi Sakaida, Emiko The combination of the tubulin binding small molecule PTC596 and proteasome inhibitors suppresses the growth of myeloma cells |
title | The combination of the tubulin binding small molecule PTC596 and proteasome inhibitors suppresses the growth of myeloma cells |
title_full | The combination of the tubulin binding small molecule PTC596 and proteasome inhibitors suppresses the growth of myeloma cells |
title_fullStr | The combination of the tubulin binding small molecule PTC596 and proteasome inhibitors suppresses the growth of myeloma cells |
title_full_unstemmed | The combination of the tubulin binding small molecule PTC596 and proteasome inhibitors suppresses the growth of myeloma cells |
title_short | The combination of the tubulin binding small molecule PTC596 and proteasome inhibitors suppresses the growth of myeloma cells |
title_sort | combination of the tubulin binding small molecule ptc596 and proteasome inhibitors suppresses the growth of myeloma cells |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7822878/ https://www.ncbi.nlm.nih.gov/pubmed/33483574 http://dx.doi.org/10.1038/s41598-021-81577-x |
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