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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: Taniguchi, Keisuke, Suzuki, Tomo, Okamura, Tomomi, Kurita, Akinobu, Nohara, Gou, Ishii, Satoru, Kado, Shoichi, Takagi, Akimitsu, Tsugane, Momomi, Shishido, Yoshiyuki
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8600181/
https://www.ncbi.nlm.nih.gov/pubmed/34804943
http://dx.doi.org/10.3389/fonc.2021.754365
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author Taniguchi, Keisuke
Suzuki, Tomo
Okamura, Tomomi
Kurita, Akinobu
Nohara, Gou
Ishii, Satoru
Kado, Shoichi
Takagi, Akimitsu
Tsugane, Momomi
Shishido, Yoshiyuki
author_facet Taniguchi, Keisuke
Suzuki, Tomo
Okamura, Tomomi
Kurita, Akinobu
Nohara, Gou
Ishii, Satoru
Kado, Shoichi
Takagi, Akimitsu
Tsugane, Momomi
Shishido, Yoshiyuki
author_sort Taniguchi, Keisuke
collection PubMed
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.
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spelling pubmed-86001812021-11-19 Perifosine, a Bioavailable Alkylphospholipid Akt Inhibitor, Exhibits Antitumor Activity in Murine Models of Cancer Brain Metastasis Through Favorable Tumor Exposure Taniguchi, Keisuke Suzuki, Tomo Okamura, Tomomi Kurita, Akinobu Nohara, Gou Ishii, Satoru Kado, Shoichi Takagi, Akimitsu Tsugane, Momomi Shishido, Yoshiyuki Front Oncol Oncology 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. Frontiers Media S.A. 2021-11-04 /pmc/articles/PMC8600181/ /pubmed/34804943 http://dx.doi.org/10.3389/fonc.2021.754365 Text en Copyright © 2021 Taniguchi, Suzuki, Okamura, Kurita, Nohara, Ishii, Kado, Takagi, Tsugane and Shishido https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Oncology
Taniguchi, Keisuke
Suzuki, Tomo
Okamura, Tomomi
Kurita, Akinobu
Nohara, Gou
Ishii, Satoru
Kado, Shoichi
Takagi, Akimitsu
Tsugane, Momomi
Shishido, Yoshiyuki
Perifosine, a Bioavailable Alkylphospholipid Akt Inhibitor, Exhibits Antitumor Activity in Murine Models of Cancer Brain Metastasis Through Favorable Tumor Exposure
title 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_short 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
topic Oncology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8600181/
https://www.ncbi.nlm.nih.gov/pubmed/34804943
http://dx.doi.org/10.3389/fonc.2021.754365
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