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.

Inhibition of Tyrosine 3-Monooxygenase/Tryptophan 5-Monooxygenase Activation Protein Zeta (YWHAZ) Overcomes Drug Resistance and Tumorigenicity in Ovarian Cancer

“…Some second-line chemotherapeutic drugs have been approved for the treatment of ovarian cancer such as paclitaxel, topotecan, etoposide, gemcitabine, and trabectedin [29]. If recurrence occurs within 6 months of the initial treatment, or if it occurs following complete clinical response to chemotherapy including platinum, liposomal paclitaxel can be used alone [30]. However, if recurrence happens after more than 6 months, liposomal paclitaxel Cellular Physiology and Biochemistry Cellular Physiology and Biochemistry may be combined with platinum for treatment.…”

Comparison of Cisplatin with Lipoplatin in Terms of Ototoxicity

“…Moreover, LIPO showed anti-tumor effect in CDDP-sensitive-and -resistant ovarian cancer cells since apoptosis was induced by caspases 3, 8, and 9 activation; Bax upregulation; and Bcl-2 downregulation [11] . LIPO caused a synergistic effect combination with doxorubicin and the albumin-bound paclitaxel abraxane.…”

“…Liposomal platinum is the most promising drug formulation under clinical conditions [11] . Lipoplatin (LIPO) is a liposomally encapsulated form of CDDP [12] .…”

Facilitating the Cellular Accumulation of Pt-Based Chemotherapeutic Drugs

“…Preclinical studies of a liposomal formulation of cisplatin have shown promising effects against ovarian, pancreatic, head and neck cancer, non-small cell lung cancer (NSCLC), and HER-2/neu–negative metastatic breast cancer [53,65,66,67,68]. In ovarian cancer, lipoplatin (liposomal cisplatin) was found to exhibit anti-tumor activity by causing caspase activation and hence apoptosis [65].…”