Preclinical evaluation of a new liposomal formulation of cisplatin, lipoplatin, to treat cisplatin-resistant cervical cancer

Naike Casagrande, Monica De Paoli, Marta Celegato, Cinzia Borghese, Maurizio Mongiat, Alfonso Colombatti, Donatella Aldinucci

Research output: Contribution to journalArticle

Abstract

Objective Cisplatin-based chemotherapy has been shown to improve survival in cervical cancer; however, treatment is associated with tumor resistance and significant toxicity. Lipoplatin is a new liposomal formulation of cisplatin, developed to reduce cisplatin toxicity, to improve drug accumulation at tumor sites and to overcome drug resistance. The aim of this study is to analyze the antitumoral activity of lipoplatin against cisplatin-resistant cervical cancer cells and to investigate its mechanism of action. Methods The activity and mechanism of action of lipoplatin were studied in the ME-180 cervical cancer cell line and its cisplatin-resistant clone R-ME-180 and HeLa cells using cell proliferation assays, flow cytometry, ELISA assay, cell migration, spheroids and tumor xenograft. Results We demonstrated that lipoplatin exhibited a potent antitumoral activity on HeLa, ME-180 cells and its cisplatin-resistant clone R-ME-180. Lipoplatin inhibited cell proliferation in a dose-dependent manner and was more active than the reference drug cisplatin in R-ME-180 cells and induced apoptosis, as evaluated by Annexin-V staining and DNA fragmentation, caspases 9 and 3 activation, Bcl-2, and Bcl-xL down-regulation, but Bax up-regulation inhibited thioredoxin reductase (TrxR) enzymatic activity and increased reactive oxygen species (ROS) accumulation; reduced EGFR expression and inhibited both migration and invasion. R-ME-180, but not ME-180 cells, generated three-dimensional (3D)-multicellular spheroids expressing the cancer stem cell marker ALDH. The ability of R-ME-180 cells to form spheroids in vitro and tumors in nude mice was also remarkably decreased by lipoplatin. Conclusions Overall, our results suggest that lipoplatin has potential for the treatment of cisplatin-resistant cervical cancer.

Original languageEnglish
Pages (from-to)744-752
Number of pages9
JournalGynecologic Oncology
Volume131
Issue number3
DOIs
Publication statusPublished - Dec 2013

Fingerprint

Uterine Cervical Neoplasms
Cisplatin
Neoplasms
Clone Cells
Cell Migration Assays
Cell Proliferation
Cellular Spheroids
Thioredoxin-Disulfide Reductase
Neoplastic Stem Cells
lipoplatin
Caspase 9
Annexin A5
DNA Fragmentation
HeLa Cells
Drug Resistance
Heterografts
Nude Mice
Caspase 3
Pharmaceutical Preparations
Reactive Oxygen Species

Keywords

  • Cancer stem cells
  • Cervical cancer
  • Cisplatin-resistance
  • Liposomal cisplatin
  • Migration
  • Spheroids

ASJC Scopus subject areas

  • Obstetrics and Gynaecology
  • Oncology

Cite this

Preclinical evaluation of a new liposomal formulation of cisplatin, lipoplatin, to treat cisplatin-resistant cervical cancer. / Casagrande, Naike; De Paoli, Monica; Celegato, Marta; Borghese, Cinzia; Mongiat, Maurizio; Colombatti, Alfonso; Aldinucci, Donatella.

In: Gynecologic Oncology, Vol. 131, No. 3, 12.2013, p. 744-752.

Research output: Contribution to journalArticle

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AU - De Paoli, Monica

AU - Celegato, Marta

AU - Borghese, Cinzia

AU - Mongiat, Maurizio

AU - Colombatti, Alfonso

AU - Aldinucci, Donatella

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N2 - Objective Cisplatin-based chemotherapy has been shown to improve survival in cervical cancer; however, treatment is associated with tumor resistance and significant toxicity. Lipoplatin is a new liposomal formulation of cisplatin, developed to reduce cisplatin toxicity, to improve drug accumulation at tumor sites and to overcome drug resistance. The aim of this study is to analyze the antitumoral activity of lipoplatin against cisplatin-resistant cervical cancer cells and to investigate its mechanism of action. Methods The activity and mechanism of action of lipoplatin were studied in the ME-180 cervical cancer cell line and its cisplatin-resistant clone R-ME-180 and HeLa cells using cell proliferation assays, flow cytometry, ELISA assay, cell migration, spheroids and tumor xenograft. Results We demonstrated that lipoplatin exhibited a potent antitumoral activity on HeLa, ME-180 cells and its cisplatin-resistant clone R-ME-180. Lipoplatin inhibited cell proliferation in a dose-dependent manner and was more active than the reference drug cisplatin in R-ME-180 cells and induced apoptosis, as evaluated by Annexin-V staining and DNA fragmentation, caspases 9 and 3 activation, Bcl-2, and Bcl-xL down-regulation, but Bax up-regulation inhibited thioredoxin reductase (TrxR) enzymatic activity and increased reactive oxygen species (ROS) accumulation; reduced EGFR expression and inhibited both migration and invasion. R-ME-180, but not ME-180 cells, generated three-dimensional (3D)-multicellular spheroids expressing the cancer stem cell marker ALDH. The ability of R-ME-180 cells to form spheroids in vitro and tumors in nude mice was also remarkably decreased by lipoplatin. Conclusions Overall, our results suggest that lipoplatin has potential for the treatment of cisplatin-resistant cervical cancer.

AB - Objective Cisplatin-based chemotherapy has been shown to improve survival in cervical cancer; however, treatment is associated with tumor resistance and significant toxicity. Lipoplatin is a new liposomal formulation of cisplatin, developed to reduce cisplatin toxicity, to improve drug accumulation at tumor sites and to overcome drug resistance. The aim of this study is to analyze the antitumoral activity of lipoplatin against cisplatin-resistant cervical cancer cells and to investigate its mechanism of action. Methods The activity and mechanism of action of lipoplatin were studied in the ME-180 cervical cancer cell line and its cisplatin-resistant clone R-ME-180 and HeLa cells using cell proliferation assays, flow cytometry, ELISA assay, cell migration, spheroids and tumor xenograft. Results We demonstrated that lipoplatin exhibited a potent antitumoral activity on HeLa, ME-180 cells and its cisplatin-resistant clone R-ME-180. Lipoplatin inhibited cell proliferation in a dose-dependent manner and was more active than the reference drug cisplatin in R-ME-180 cells and induced apoptosis, as evaluated by Annexin-V staining and DNA fragmentation, caspases 9 and 3 activation, Bcl-2, and Bcl-xL down-regulation, but Bax up-regulation inhibited thioredoxin reductase (TrxR) enzymatic activity and increased reactive oxygen species (ROS) accumulation; reduced EGFR expression and inhibited both migration and invasion. R-ME-180, but not ME-180 cells, generated three-dimensional (3D)-multicellular spheroids expressing the cancer stem cell marker ALDH. The ability of R-ME-180 cells to form spheroids in vitro and tumors in nude mice was also remarkably decreased by lipoplatin. Conclusions Overall, our results suggest that lipoplatin has potential for the treatment of cisplatin-resistant cervical cancer.

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KW - Migration

KW - Spheroids

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