The combination of the tubulin binding small molecule PTC596 and proteasome inhibitors suppresses the growth of myeloma cells
Abstract 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)...
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Nature Portfolio
2021
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oai:doaj.org-article:481913bfae7549a8909dc48c57cf66bb2021-12-02T15:23:39ZThe combination of the tubulin binding small molecule PTC596 and proteasome inhibitors suppresses the growth of myeloma cells10.1038/s41598-021-81577-x2045-2322https://doaj.org/article/481913bfae7549a8909dc48c57cf66bb2021-01-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-81577-xhttps://doaj.org/toc/2045-2322Abstract 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.Yurie NagaiNaoya MimuraOla RizqYusuke IsshikiMotohiko OshimaMohamed RizkAtsunori SarayaShuhei KoideYaeko Nakajima-TakagiMakiko MiyotaTetsuhiro ChibaNagisa Oshima-HasegawaTomoya MutoShokichi TsukamotoShio MitsukawaYusuke TakedaChikako OhwadaMasahiro TakeuchiTohru IsekiChiaki NakasekoWilliam LennoxJosephine SheedyMarla WeetallKoutaro YokoteAtsushi IwamaEmiko SakaidaNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-14 (2021) |
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Medicine R Science Q Yurie Nagai Naoya Mimura Ola Rizq Yusuke Isshiki Motohiko Oshima Mohamed Rizk Atsunori Saraya Shuhei Koide Yaeko Nakajima-Takagi Makiko Miyota Tetsuhiro Chiba Nagisa Oshima-Hasegawa Tomoya Muto Shokichi Tsukamoto Shio Mitsukawa Yusuke Takeda Chikako Ohwada Masahiro Takeuchi Tohru Iseki Chiaki Nakaseko William Lennox Josephine Sheedy Marla Weetall Koutaro Yokote Atsushi Iwama Emiko Sakaida The combination of the tubulin binding small molecule PTC596 and proteasome inhibitors suppresses the growth of myeloma cells |
| description |
Abstract 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 |
article |
| author |
Yurie Nagai Naoya Mimura Ola Rizq Yusuke Isshiki Motohiko Oshima Mohamed Rizk Atsunori Saraya Shuhei Koide Yaeko Nakajima-Takagi Makiko Miyota Tetsuhiro Chiba Nagisa Oshima-Hasegawa Tomoya Muto Shokichi Tsukamoto Shio Mitsukawa Yusuke Takeda Chikako Ohwada Masahiro Takeuchi Tohru Iseki Chiaki Nakaseko William Lennox Josephine Sheedy Marla Weetall Koutaro Yokote Atsushi Iwama Emiko Sakaida |
| author_facet |
Yurie Nagai Naoya Mimura Ola Rizq Yusuke Isshiki Motohiko Oshima Mohamed Rizk Atsunori Saraya Shuhei Koide Yaeko Nakajima-Takagi Makiko Miyota Tetsuhiro Chiba Nagisa Oshima-Hasegawa Tomoya Muto Shokichi Tsukamoto Shio Mitsukawa Yusuke Takeda Chikako Ohwada Masahiro Takeuchi Tohru Iseki Chiaki Nakaseko William Lennox Josephine Sheedy Marla Weetall Koutaro Yokote Atsushi Iwama Emiko Sakaida |
| author_sort |
Yurie Nagai |
| title |
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_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_sort |
combination of the tubulin binding small molecule ptc596 and proteasome inhibitors suppresses the growth of myeloma cells |
| publisher |
Nature Portfolio |
| publishDate |
2021 |
| url |
https://doaj.org/article/481913bfae7549a8909dc48c57cf66bb |
| work_keys_str_mv |
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