Vorinostat potentiates 5-fluorouracil/cisplatin combination by inhibiting chemotherapy-induced EGFR nuclear translocation and increasing cisplatin uptake

Geny Piro, Maria Serena Roca, Francesca Bruzzese, Carmine Carbone, Federica Iannelli, Alessandra Leone, Maria Grazia Volpe, Alfredo Budillon, Elena Di Gennaro

Research output: Contribution to journalArticle

Abstract

The 5-fluorouracil/cisplatin (5FU/CDDP) combination is one of the most widely used treatment options for several solid tumors. However, despite good anticancer responses, this regimen is often associated with high toxicity and treatment resistance. In our study, we evaluated whether the histone deacetylase inhibitor (HDACi), vorinostat, may induce synergistic antitumor and proapoptotic effects in combination with 5FU/CDDP in squamous cancer cell models. We demonstrated in cancer cell lines, including the intrinsic CDDP-resistant Cal27 cells, that simultaneous exposure to equitoxic doses of vorinostat plus 5FU/CDDP results in strong synergistic antiproliferative and proapoptotic effects related to cell-cycle perturbation and DNA damage induction. These effects were confirmed in vivo in both orthotopic and heterotopic xenograft mouse models of Cal27 cells. Mechanistically, vorinostat reverted 5FU/CDDP-induced EGFR phosphorylation and nuclear translocation, leading to the impairment of nuclear EGFR noncanonical induction of genes such as thymidylate synthase and cyclin D1. These effects were exerted by vorinostat, at least in part, by increasing lysosomal-mediated EGFR protein degradation. Moreover, vorinostat increased platinum uptake and platinated DNA levels by transcriptionally upregulating the CDDP influx channel copper transporter 1 (CTR1). Overall, to our knowledge, this study is the first to demonstrate the ability of vorinostat to inhibit two well-known mechanisms of CDDP resistance, EGFR nuclear translocation and CTR1 overexpression, adding new insight into the mechanism of the synergistic interaction between HDACi- and CDDP-based chemotherapy and providing the rationale to clinically explore this combination to overcome dose-limiting toxicity and chemotherapy resistance.

Original languageEnglish
Pages (from-to)1405-1417
Number of pages13
JournalMolecular Cancer Therapeutics
Volume18
Issue number8
DOIs
Publication statusPublished - Jan 1 2019

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Combination Drug Therapy
Fluorouracil
Cisplatin
Histone Deacetylase Inhibitors
Drug Therapy
Squamous Cell Neoplasms
Thymidylate Synthase
Cyclin D1
Platinum
Heterografts
Proteolysis
DNA Damage
vorinostat
Neoplasms
Cell Cycle
Phosphorylation
Cell Line
DNA
Therapeutics
Genes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

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title = "Vorinostat potentiates 5-fluorouracil/cisplatin combination by inhibiting chemotherapy-induced EGFR nuclear translocation and increasing cisplatin uptake",
abstract = "The 5-fluorouracil/cisplatin (5FU/CDDP) combination is one of the most widely used treatment options for several solid tumors. However, despite good anticancer responses, this regimen is often associated with high toxicity and treatment resistance. In our study, we evaluated whether the histone deacetylase inhibitor (HDACi), vorinostat, may induce synergistic antitumor and proapoptotic effects in combination with 5FU/CDDP in squamous cancer cell models. We demonstrated in cancer cell lines, including the intrinsic CDDP-resistant Cal27 cells, that simultaneous exposure to equitoxic doses of vorinostat plus 5FU/CDDP results in strong synergistic antiproliferative and proapoptotic effects related to cell-cycle perturbation and DNA damage induction. These effects were confirmed in vivo in both orthotopic and heterotopic xenograft mouse models of Cal27 cells. Mechanistically, vorinostat reverted 5FU/CDDP-induced EGFR phosphorylation and nuclear translocation, leading to the impairment of nuclear EGFR noncanonical induction of genes such as thymidylate synthase and cyclin D1. These effects were exerted by vorinostat, at least in part, by increasing lysosomal-mediated EGFR protein degradation. Moreover, vorinostat increased platinum uptake and platinated DNA levels by transcriptionally upregulating the CDDP influx channel copper transporter 1 (CTR1). Overall, to our knowledge, this study is the first to demonstrate the ability of vorinostat to inhibit two well-known mechanisms of CDDP resistance, EGFR nuclear translocation and CTR1 overexpression, adding new insight into the mechanism of the synergistic interaction between HDACi- and CDDP-based chemotherapy and providing the rationale to clinically explore this combination to overcome dose-limiting toxicity and chemotherapy resistance.",
author = "Geny Piro and Roca, {Maria Serena} and Francesca Bruzzese and Carmine Carbone and Federica Iannelli and Alessandra Leone and Volpe, {Maria Grazia} and Alfredo Budillon and {Di Gennaro}, Elena",
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T1 - Vorinostat potentiates 5-fluorouracil/cisplatin combination by inhibiting chemotherapy-induced EGFR nuclear translocation and increasing cisplatin uptake

AU - Piro, Geny

AU - Roca, Maria Serena

AU - Bruzzese, Francesca

AU - Carbone, Carmine

AU - Iannelli, Federica

AU - Leone, Alessandra

AU - Volpe, Maria Grazia

AU - Budillon, Alfredo

AU - Di Gennaro, Elena

PY - 2019/1/1

Y1 - 2019/1/1

N2 - The 5-fluorouracil/cisplatin (5FU/CDDP) combination is one of the most widely used treatment options for several solid tumors. However, despite good anticancer responses, this regimen is often associated with high toxicity and treatment resistance. In our study, we evaluated whether the histone deacetylase inhibitor (HDACi), vorinostat, may induce synergistic antitumor and proapoptotic effects in combination with 5FU/CDDP in squamous cancer cell models. We demonstrated in cancer cell lines, including the intrinsic CDDP-resistant Cal27 cells, that simultaneous exposure to equitoxic doses of vorinostat plus 5FU/CDDP results in strong synergistic antiproliferative and proapoptotic effects related to cell-cycle perturbation and DNA damage induction. These effects were confirmed in vivo in both orthotopic and heterotopic xenograft mouse models of Cal27 cells. Mechanistically, vorinostat reverted 5FU/CDDP-induced EGFR phosphorylation and nuclear translocation, leading to the impairment of nuclear EGFR noncanonical induction of genes such as thymidylate synthase and cyclin D1. These effects were exerted by vorinostat, at least in part, by increasing lysosomal-mediated EGFR protein degradation. Moreover, vorinostat increased platinum uptake and platinated DNA levels by transcriptionally upregulating the CDDP influx channel copper transporter 1 (CTR1). Overall, to our knowledge, this study is the first to demonstrate the ability of vorinostat to inhibit two well-known mechanisms of CDDP resistance, EGFR nuclear translocation and CTR1 overexpression, adding new insight into the mechanism of the synergistic interaction between HDACi- and CDDP-based chemotherapy and providing the rationale to clinically explore this combination to overcome dose-limiting toxicity and chemotherapy resistance.

AB - The 5-fluorouracil/cisplatin (5FU/CDDP) combination is one of the most widely used treatment options for several solid tumors. However, despite good anticancer responses, this regimen is often associated with high toxicity and treatment resistance. In our study, we evaluated whether the histone deacetylase inhibitor (HDACi), vorinostat, may induce synergistic antitumor and proapoptotic effects in combination with 5FU/CDDP in squamous cancer cell models. We demonstrated in cancer cell lines, including the intrinsic CDDP-resistant Cal27 cells, that simultaneous exposure to equitoxic doses of vorinostat plus 5FU/CDDP results in strong synergistic antiproliferative and proapoptotic effects related to cell-cycle perturbation and DNA damage induction. These effects were confirmed in vivo in both orthotopic and heterotopic xenograft mouse models of Cal27 cells. Mechanistically, vorinostat reverted 5FU/CDDP-induced EGFR phosphorylation and nuclear translocation, leading to the impairment of nuclear EGFR noncanonical induction of genes such as thymidylate synthase and cyclin D1. These effects were exerted by vorinostat, at least in part, by increasing lysosomal-mediated EGFR protein degradation. Moreover, vorinostat increased platinum uptake and platinated DNA levels by transcriptionally upregulating the CDDP influx channel copper transporter 1 (CTR1). Overall, to our knowledge, this study is the first to demonstrate the ability of vorinostat to inhibit two well-known mechanisms of CDDP resistance, EGFR nuclear translocation and CTR1 overexpression, adding new insight into the mechanism of the synergistic interaction between HDACi- and CDDP-based chemotherapy and providing the rationale to clinically explore this combination to overcome dose-limiting toxicity and chemotherapy resistance.

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