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Improving anti-tumor efficacy of low-dose Vincristine in rhabdomyosarcoma via the combination therapy with FOXM1 inhibitor RCM1

Rhabdomyosarcoma (RMS) is a highly metastatic soft-tissue sarcoma that often develops resistance to current therapies, including vincristine. Since the existing treatments have not significantly improved survival, there is a critical need for new therapeutic approaches for RMS patients. FOXM1, a kno...

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Autores principales: Donovan, Johnny, Deng, Zicheng, Bian, Fenghua, Shukla, Samriddhi, Gomez-Arroyo, Jose, Shi, Donglu, Kalinichenko, Vladimir V., Kalin, Tanya V.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9933126/
https://www.ncbi.nlm.nih.gov/pubmed/36816948
http://dx.doi.org/10.3389/fonc.2023.1112859
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author Donovan, Johnny
Deng, Zicheng
Bian, Fenghua
Shukla, Samriddhi
Gomez-Arroyo, Jose
Shi, Donglu
Kalinichenko, Vladimir V.
Kalin, Tanya V.
author_facet Donovan, Johnny
Deng, Zicheng
Bian, Fenghua
Shukla, Samriddhi
Gomez-Arroyo, Jose
Shi, Donglu
Kalinichenko, Vladimir V.
Kalin, Tanya V.
author_sort Donovan, Johnny
collection PubMed
description Rhabdomyosarcoma (RMS) is a highly metastatic soft-tissue sarcoma that often develops resistance to current therapies, including vincristine. Since the existing treatments have not significantly improved survival, there is a critical need for new therapeutic approaches for RMS patients. FOXM1, a known oncogene, is highly expressed in RMS, and is associated with the worst prognosis in RMS patients. In the present study, we found that the combination treatment with specific FOXM1 inhibitor RCM1 and low doses of vincristine is more effective in increasing apoptosis and decreasing RMS cell proliferation in vitro compared to single drugs alone. Since RCM1 is highly hydrophobic, we developed innovative nanoparticle delivery system containing poly-beta-amino-esters and folic acid (NP(FA)), which efficiently delivers RCM1 to mouse RMS tumors in vivo. The combination of low doses of vincristine together with intravenous administration of NP(FA) nanoparticles containing RCM1 effectively reduced RMS tumor volumes, increased tumor cell death and decreased tumor cell proliferation in RMS tumors compared to RCM1 or vincristine alone. The combination therapy was non-toxic as demonstrated by liver metabolic panels using peripheral blood serum. Using RNA-seq of dissected RMS tumors, we identified Chac1 as a uniquely downregulated gene after the combination treatment. Knockdown of Chac1 in RMS cells in vitro recapitulated the effects of the combination therapy. Altogether, combination treatment with low doses of vincristine and nanoparticle delivery of FOXM1 inhibitor RCM1 in a pre-clinical model of RMS has superior anti-tumor effects and decreases CHAC1 while reducing vincristine toxicity.
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spelling pubmed-99331262023-02-17 Improving anti-tumor efficacy of low-dose Vincristine in rhabdomyosarcoma via the combination therapy with FOXM1 inhibitor RCM1 Donovan, Johnny Deng, Zicheng Bian, Fenghua Shukla, Samriddhi Gomez-Arroyo, Jose Shi, Donglu Kalinichenko, Vladimir V. Kalin, Tanya V. Front Oncol Oncology Rhabdomyosarcoma (RMS) is a highly metastatic soft-tissue sarcoma that often develops resistance to current therapies, including vincristine. Since the existing treatments have not significantly improved survival, there is a critical need for new therapeutic approaches for RMS patients. FOXM1, a known oncogene, is highly expressed in RMS, and is associated with the worst prognosis in RMS patients. In the present study, we found that the combination treatment with specific FOXM1 inhibitor RCM1 and low doses of vincristine is more effective in increasing apoptosis and decreasing RMS cell proliferation in vitro compared to single drugs alone. Since RCM1 is highly hydrophobic, we developed innovative nanoparticle delivery system containing poly-beta-amino-esters and folic acid (NP(FA)), which efficiently delivers RCM1 to mouse RMS tumors in vivo. The combination of low doses of vincristine together with intravenous administration of NP(FA) nanoparticles containing RCM1 effectively reduced RMS tumor volumes, increased tumor cell death and decreased tumor cell proliferation in RMS tumors compared to RCM1 or vincristine alone. The combination therapy was non-toxic as demonstrated by liver metabolic panels using peripheral blood serum. Using RNA-seq of dissected RMS tumors, we identified Chac1 as a uniquely downregulated gene after the combination treatment. Knockdown of Chac1 in RMS cells in vitro recapitulated the effects of the combination therapy. Altogether, combination treatment with low doses of vincristine and nanoparticle delivery of FOXM1 inhibitor RCM1 in a pre-clinical model of RMS has superior anti-tumor effects and decreases CHAC1 while reducing vincristine toxicity. Frontiers Media S.A. 2023-02-02 /pmc/articles/PMC9933126/ /pubmed/36816948 http://dx.doi.org/10.3389/fonc.2023.1112859 Text en Copyright © 2023 Donovan, Deng, Bian, Shukla, Gomez-Arroyo, Shi, Kalinichenko and Kalin 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
Donovan, Johnny
Deng, Zicheng
Bian, Fenghua
Shukla, Samriddhi
Gomez-Arroyo, Jose
Shi, Donglu
Kalinichenko, Vladimir V.
Kalin, Tanya V.
Improving anti-tumor efficacy of low-dose Vincristine in rhabdomyosarcoma via the combination therapy with FOXM1 inhibitor RCM1
title Improving anti-tumor efficacy of low-dose Vincristine in rhabdomyosarcoma via the combination therapy with FOXM1 inhibitor RCM1
title_full Improving anti-tumor efficacy of low-dose Vincristine in rhabdomyosarcoma via the combination therapy with FOXM1 inhibitor RCM1
title_fullStr Improving anti-tumor efficacy of low-dose Vincristine in rhabdomyosarcoma via the combination therapy with FOXM1 inhibitor RCM1
title_full_unstemmed Improving anti-tumor efficacy of low-dose Vincristine in rhabdomyosarcoma via the combination therapy with FOXM1 inhibitor RCM1
title_short Improving anti-tumor efficacy of low-dose Vincristine in rhabdomyosarcoma via the combination therapy with FOXM1 inhibitor RCM1
title_sort improving anti-tumor efficacy of low-dose vincristine in rhabdomyosarcoma via the combination therapy with foxm1 inhibitor rcm1
topic Oncology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9933126/
https://www.ncbi.nlm.nih.gov/pubmed/36816948
http://dx.doi.org/10.3389/fonc.2023.1112859
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