In ovarian cancer maraviroc potentiates the antitumoral activity and further inhibits the formation of a tumor-promoting microenvironment by trabectedin
Ovarian cancer (OC) is the fifth most frequent cause of cancer-related death in women. Chemotherapy agent trabectedin, affecting cancer cells and tumor microenvironment, has been approved for the treatment of relapsed platinum-sensitive OC patients. CCR5-antagonist maraviroc inhibits tumor growth, m...
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| Format: | Article |
| Language: | English |
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Elsevier
2024-03-01
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| Series: | Biomedicine & Pharmacotherapy |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S075333222400177X |
| _version_ | 1797291823329181696 |
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| author | Naike Casagrande Cinzia Borghese Giuseppe Corona Donatella Aldinucci |
| author_facet | Naike Casagrande Cinzia Borghese Giuseppe Corona Donatella Aldinucci |
| author_sort | Naike Casagrande |
| collection | DOAJ |
| description | Ovarian cancer (OC) is the fifth most frequent cause of cancer-related death in women. Chemotherapy agent trabectedin, affecting cancer cells and tumor microenvironment, has been approved for the treatment of relapsed platinum-sensitive OC patients. CCR5-antagonist maraviroc inhibits tumor growth, metastasis, and enhances the antitumoral activity of DNA-damaging drugs. Here, we found that OC cells expressed CCR5 receptor but did not secret CCR5-ligands. Maraviroc treatment did not affect OC cell viability, but strongly potentiated the antiproliferative activity, apoptosis induction, cell cycle blockage, DNA damage, and ROS formation by trabectedin. In A2780cis cisplatin-resistant cells, the cross-resistance to trabectedin was overcame by the combination with maraviroc. Maraviroc enhanced trabectedin cytotoxicity in OC 3Dimensional spheroids and THP-1-monocytes. Both maraviroc and trabectedin interact with drug efflux pump MDR1/P-gp, overexpressed in recurrent OC patients. Maraviroc increased trabectedin intracellular accumulation and the MDR1-inhibitor verapamil, like maraviroc, increased trabectedin cytotoxicity. In OC tumor xenografts the combination with maraviroc further reduced tumor growth, angiogenesis, and monocyte infiltration by trabectedin. In conclusion, this study offers a preclinical rationale for the use of maraviroc as new option to improve trabectedin activity in relapsed chemoresistant OC patients. |
| first_indexed | 2024-03-07T19:42:23Z |
| format | Article |
| id | doaj.art-4443b403b3c04ebe805c284f263a4aa9 |
| institution | Directory Open Access Journal |
| issn | 0753-3322 |
| language | English |
| last_indexed | 2024-03-07T19:42:23Z |
| publishDate | 2024-03-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Biomedicine & Pharmacotherapy |
| spelling | doaj.art-4443b403b3c04ebe805c284f263a4aa92024-02-29T05:18:01ZengElsevierBiomedicine & Pharmacotherapy0753-33222024-03-01172116296In ovarian cancer maraviroc potentiates the antitumoral activity and further inhibits the formation of a tumor-promoting microenvironment by trabectedinNaike Casagrande0Cinzia Borghese1Giuseppe Corona2Donatella Aldinucci3Molecular Oncology, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, Aviano, PN 33081, Italy; Correspondence to: Molecular Oncology Unit, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, Via F. Gallini 2, Aviano, PN 33081, Italy.Molecular Oncology, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, Aviano, PN 33081, ItalyImmunopathology and Cancer Biomarkers Unit, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, Aviano, PN 33081, ItalyMolecular Oncology, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, Aviano, PN 33081, ItalyOvarian cancer (OC) is the fifth most frequent cause of cancer-related death in women. Chemotherapy agent trabectedin, affecting cancer cells and tumor microenvironment, has been approved for the treatment of relapsed platinum-sensitive OC patients. CCR5-antagonist maraviroc inhibits tumor growth, metastasis, and enhances the antitumoral activity of DNA-damaging drugs. Here, we found that OC cells expressed CCR5 receptor but did not secret CCR5-ligands. Maraviroc treatment did not affect OC cell viability, but strongly potentiated the antiproliferative activity, apoptosis induction, cell cycle blockage, DNA damage, and ROS formation by trabectedin. In A2780cis cisplatin-resistant cells, the cross-resistance to trabectedin was overcame by the combination with maraviroc. Maraviroc enhanced trabectedin cytotoxicity in OC 3Dimensional spheroids and THP-1-monocytes. Both maraviroc and trabectedin interact with drug efflux pump MDR1/P-gp, overexpressed in recurrent OC patients. Maraviroc increased trabectedin intracellular accumulation and the MDR1-inhibitor verapamil, like maraviroc, increased trabectedin cytotoxicity. In OC tumor xenografts the combination with maraviroc further reduced tumor growth, angiogenesis, and monocyte infiltration by trabectedin. In conclusion, this study offers a preclinical rationale for the use of maraviroc as new option to improve trabectedin activity in relapsed chemoresistant OC patients.http://www.sciencedirect.com/science/article/pii/S075333222400177XOvarian cancerCCR5-antagonist maravirocTrabectedinm MDR1/P-glycoproteinTumor microenvironment |
| spellingShingle | Naike Casagrande Cinzia Borghese Giuseppe Corona Donatella Aldinucci In ovarian cancer maraviroc potentiates the antitumoral activity and further inhibits the formation of a tumor-promoting microenvironment by trabectedin Biomedicine & Pharmacotherapy Ovarian cancer CCR5-antagonist maraviroc Trabectedinm MDR1/P-glycoprotein Tumor microenvironment |
| title | In ovarian cancer maraviroc potentiates the antitumoral activity and further inhibits the formation of a tumor-promoting microenvironment by trabectedin |
| title_full | In ovarian cancer maraviroc potentiates the antitumoral activity and further inhibits the formation of a tumor-promoting microenvironment by trabectedin |
| title_fullStr | In ovarian cancer maraviroc potentiates the antitumoral activity and further inhibits the formation of a tumor-promoting microenvironment by trabectedin |
| title_full_unstemmed | In ovarian cancer maraviroc potentiates the antitumoral activity and further inhibits the formation of a tumor-promoting microenvironment by trabectedin |
| title_short | In ovarian cancer maraviroc potentiates the antitumoral activity and further inhibits the formation of a tumor-promoting microenvironment by trabectedin |
| title_sort | in ovarian cancer maraviroc potentiates the antitumoral activity and further inhibits the formation of a tumor promoting microenvironment by trabectedin |
| topic | Ovarian cancer CCR5-antagonist maraviroc Trabectedinm MDR1/P-glycoprotein Tumor microenvironment |
| url | http://www.sciencedirect.com/science/article/pii/S075333222400177X |
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