Preclinical activity of the liposomal cisplatin lipoplatin in ovarian cancer.

Abstract

PURPOSE:

Cisplatin and its platinum derivatives are first-line chemotherapeutic agents in the treatment of ovarian cancer; however, treatment is associated with tumor resistance and significant toxicity. Here we investigated the antitumoral activity of lipoplatin, one of the most promising liposomal platinum drug formulations under clinical investigation.

EXPERIMENTAL DESIGN:

In vitro effects of lipoplatin were tested on a panel of ovarian cancer cell lines, sensitive and resistant to cisplatin, using both two-dimensional (2D) and 3D cell models. We evaluated in vivo the lipoplatin anticancer activity using tumor xenografts.

RESULTS:

Lipoplatin exhibited a potent antitumoral activity in all ovarian cancer cell lines tested, induced apoptosis, and activated caspase-9, -8, and -3, downregulating Bcl-2 and upregulating Bax. Lipoplatin inhibited thioredoxin reductase enzymatic activity and increased reactive oxygen species accumulation and reduced EGF receptor (EGFR) expression and inhibited cell invasion. Lipoplatin demonstrated a synergistic effect when used in combination with doxorubicin, widely used in relapsed ovarian cancer treatment, and with the albumin-bound paclitaxel, Abraxane. Lipoplatin decreased both ALDH and CD133 expression, markers of ovarian cancer stem cells. Multicellular aggregates/spheroids are present in ascites of patients and most contribute to the spreading to secondary sites. Lipoplatin decreased spheroids growth, vitality, and cell migration out of preformed spheroids. Finally, lipoplatin inhibited more than 90% tumor xenograft growth with minimal systemic toxicity, and after the treatment suspension, no tumor progression was observed.

CONCLUSION:

These preclinical data suggest that lipoplatin has potential for clinical assessment in aggressive cisplatin-resistant patients with ovarian cancer.

• Authors: Naike Casagrande, Marta Celegato, Cinzia Borghese, Maurizio Mongiat, Alfonso Colombatti, Donatella Aldinucci
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 20 Issue 21 Pg. 5496-506 (Nov 01 2014) ISSN: 1557-3265 [Electronic] United States
• PMID: 25231401 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: ©2014 American Association for Cancer Research.

Chemical References

• AC133 Antigen
• Albumin-Bound Paclitaxel
• Albumins
• Antigens, CD
• Antineoplastic Agents
• Glycoproteins
• Liposomes
• PROM1 protein, human
• Peptides
• Proto-Oncogene Proteins c-bcl-2
• Reactive Oxygen Species
• bcl-2-Associated X Protein
• lipoplatin
• Doxorubicin
• EGFR protein, human
• ErbB Receptors
• Caspases
• Paclitaxel
• Cisplatin

Topics

• AC133 Antigen
• Albumin-Bound Paclitaxel
• Albumins (pharmacology)
• Antigens, CD (genetics, metabolism)
• Antineoplastic Agents (pharmacology)
• Caspases (genetics, metabolism)
• Cell Line, Tumor
• Cell Movement (drug effects, genetics)
• Cisplatin (pharmacology)
• Down-Regulation (drug effects, genetics)
• Doxorubicin (pharmacology)
• Drug Resistance, Neoplasm (drug effects, genetics)
• ErbB Receptors (genetics, metabolism)
• Female
• Glycoproteins (genetics, metabolism)
• Humans
• Liposomes (pharmacology)
• Neoplasm Invasiveness (genetics)
• Ovarian Neoplasms (drug therapy, genetics, metabolism)
• Paclitaxel (pharmacology)
• Peptides (genetics, metabolism)
• Proto-Oncogene Proteins c-bcl-2 (genetics, metabolism)
• Reactive Oxygen Species (metabolism)
• Spheroids, Cellular (drug effects, metabolism)
• Up-Regulation (drug effects, genetics)
• bcl-2-Associated X Protein (genetics, metabolism)