Perifosine, a Bioavailable Alkylphospholipid Akt Inhibitor, Exhibits Antitumor Activity in Murine Models of Cancer Brain Metastasis Through Favorable Tumor Exposure

Metastatic brain tumors are regarded as the most advanced stage of certain types of cancer; however, chemotherapy has played a limited role in the treatment of brain metastases. Here, we established murine models of brain metastasis using cell lines derived from human brain metastatic tumors, and ai...

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Autores principales:	Keisuke Taniguchi, Tomo Suzuki, Tomomi Okamura, Akinobu Kurita, Gou Nohara, Satoru Ishii, Shoichi Kado, Akimitsu Takagi, Momomi Tsugane, Yoshiyuki Shishido
Formato:	article
Lenguaje:	EN
Publicado:	Frontiers Media S.A. 2021
Materias:	brain cancer metastasis signaling pathway PI3K AKT apoptosis Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
Acceso en línea:	https://doaj.org/article/39157eec5a8c4744ab579f8c951d9381
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spelling	oai:doaj.org-article:39157eec5a8c4744ab579f8c951d93812021-11-04T08:22:05ZPerifosine, a Bioavailable Alkylphospholipid Akt Inhibitor, Exhibits Antitumor Activity in Murine Models of Cancer Brain Metastasis Through Favorable Tumor Exposure2234-943X10.3389/fonc.2021.754365https://doaj.org/article/39157eec5a8c4744ab579f8c951d93812021-11-01T00:00:00Zhttps://www.frontiersin.org/articles/10.3389/fonc.2021.754365/fullhttps://doaj.org/toc/2234-943XMetastatic brain tumors are regarded as the most advanced stage of certain types of cancer; however, chemotherapy has played a limited role in the treatment of brain metastases. Here, we established murine models of brain metastasis using cell lines derived from human brain metastatic tumors, and aimed to explore the antitumor efficacy of perifosine, an orally active allosteric Akt inhibitor. We evaluated the effectiveness of perifosine by using it as a single agent in ectopic and orthotopic models created by injecting the DU 145 and NCI-H1915 cell lines into mice. Initially, the injected cells formed distant multifocal lesions in the brains of NCI-H1915 mice, making surgical resection impractical in clinical settings. We determined that perifosine could distribute into the brain and remain localized in that region for a long period. Perifosine significantly prolonged the survival of DU 145 and NCI-H1915 orthotopic brain tumor mice; additionally, complete tumor regression was observed in the NCI-H1915 model. Perifosine also elicited much stronger antitumor responses against subcutaneous NCI-H1915 growth; a similar trend of sensitivity to perifosine was also observed in the orthotopic models. Moreover, the degree of suppression of NCI-H1915 tumor growth was associated with long-term exposure to a high level of perifosine at the tumor site and the resultant blockage of the PI3K/Akt signaling pathway, a decrease in tumor cell proliferation, and increased apoptosis. The results presented here provide a promising approach for the future treatment of patients with metastatic brain cancers and emphasize the importance of enriching a patient population that has a higher probability of responding to perifosine.Keisuke TaniguchiTomo SuzukiTomomi OkamuraAkinobu KuritaGou NoharaSatoru IshiiShoichi KadoAkimitsu TakagiMomomi TsuganeYoshiyuki ShishidoFrontiers Media S.A.articlebrain cancermetastasissignaling pathwayPI3KAKTapoptosisNeoplasms. Tumors. Oncology. Including cancer and carcinogensRC254-282ENFrontiers in Oncology, Vol 11 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	brain cancer metastasis signaling pathway PI3K AKT apoptosis Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
spellingShingle	brain cancer metastasis signaling pathway PI3K AKT apoptosis Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282 Keisuke Taniguchi Tomo Suzuki Tomomi Okamura Akinobu Kurita Gou Nohara Satoru Ishii Shoichi Kado Akimitsu Takagi Momomi Tsugane Yoshiyuki Shishido Perifosine, a Bioavailable Alkylphospholipid Akt Inhibitor, Exhibits Antitumor Activity in Murine Models of Cancer Brain Metastasis Through Favorable Tumor Exposure
description	Metastatic brain tumors are regarded as the most advanced stage of certain types of cancer; however, chemotherapy has played a limited role in the treatment of brain metastases. Here, we established murine models of brain metastasis using cell lines derived from human brain metastatic tumors, and aimed to explore the antitumor efficacy of perifosine, an orally active allosteric Akt inhibitor. We evaluated the effectiveness of perifosine by using it as a single agent in ectopic and orthotopic models created by injecting the DU 145 and NCI-H1915 cell lines into mice. Initially, the injected cells formed distant multifocal lesions in the brains of NCI-H1915 mice, making surgical resection impractical in clinical settings. We determined that perifosine could distribute into the brain and remain localized in that region for a long period. Perifosine significantly prolonged the survival of DU 145 and NCI-H1915 orthotopic brain tumor mice; additionally, complete tumor regression was observed in the NCI-H1915 model. Perifosine also elicited much stronger antitumor responses against subcutaneous NCI-H1915 growth; a similar trend of sensitivity to perifosine was also observed in the orthotopic models. Moreover, the degree of suppression of NCI-H1915 tumor growth was associated with long-term exposure to a high level of perifosine at the tumor site and the resultant blockage of the PI3K/Akt signaling pathway, a decrease in tumor cell proliferation, and increased apoptosis. The results presented here provide a promising approach for the future treatment of patients with metastatic brain cancers and emphasize the importance of enriching a patient population that has a higher probability of responding to perifosine.
format	article
author	Keisuke Taniguchi Tomo Suzuki Tomomi Okamura Akinobu Kurita Gou Nohara Satoru Ishii Shoichi Kado Akimitsu Takagi Momomi Tsugane Yoshiyuki Shishido
author_facet	Keisuke Taniguchi Tomo Suzuki Tomomi Okamura Akinobu Kurita Gou Nohara Satoru Ishii Shoichi Kado Akimitsu Takagi Momomi Tsugane Yoshiyuki Shishido
author_sort	Keisuke Taniguchi
title	Perifosine, a Bioavailable Alkylphospholipid Akt Inhibitor, Exhibits Antitumor Activity in Murine Models of Cancer Brain Metastasis Through Favorable Tumor Exposure
title_short	Perifosine, a Bioavailable Alkylphospholipid Akt Inhibitor, Exhibits Antitumor Activity in Murine Models of Cancer Brain Metastasis Through Favorable Tumor Exposure
title_full	Perifosine, a Bioavailable Alkylphospholipid Akt Inhibitor, Exhibits Antitumor Activity in Murine Models of Cancer Brain Metastasis Through Favorable Tumor Exposure
title_fullStr	Perifosine, a Bioavailable Alkylphospholipid Akt Inhibitor, Exhibits Antitumor Activity in Murine Models of Cancer Brain Metastasis Through Favorable Tumor Exposure
title_full_unstemmed	Perifosine, a Bioavailable Alkylphospholipid Akt Inhibitor, Exhibits Antitumor Activity in Murine Models of Cancer Brain Metastasis Through Favorable Tumor Exposure
title_sort	perifosine, a bioavailable alkylphospholipid akt inhibitor, exhibits antitumor activity in murine models of cancer brain metastasis through favorable tumor exposure
publisher	Frontiers Media S.A.
publishDate	2021
url	https://doaj.org/article/39157eec5a8c4744ab579f8c951d9381
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Perifosine, a Bioavailable Alkylphospholipid Akt Inhibitor, Exhibits Antitumor Activity in Murine Models of Cancer Brain Metastasis Through Favorable Tumor Exposure

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