Use of lonidamine to potentiate the effect of cisplatin and carboplatin on platinum resistant human ovarian cancer cells

Abstract

Lonidamine (LND), an indazole-3-carboxylic-acid derivative, is a new, relatively non-toxic, chemotherapeutic agent. LND, which interferes with energy metabolism, has been shown to potentiate the antineoplastic effects of chemotherapeutic agents and radiation. In this study, we evaluated the effect of LND in combination with cisplatin (DDP) or carboplatin (CARBO) on platinum resistant ovarian cancer cells. The ovarian cancer cell line BG-1 was selected as platinum resistant cell line, defined as cell line with survival fraction >50% at 0.5 peak plasma concentration (PPC). Cells were treated during the proliferative phase of cell growth with DDP and CARBO using doses between 0.1 and 1x (x = PPC). PPC of DDP = 2.5 mu g/ml, PPC of CARBO = 28 mu g/ml. Cells were also treated with LND at doses varying between 10 and 100 mu g/ml (PPC 20-50 mu g/ml). Drugs were used as single agents and in combination. Experiments were performed by treating the cells with DDP or CARBO for 90 min and with LND continuous exposure or 90 min only. The ATP cell viability assay was used to assess the antiproliferative effect of the drugs tested. Experiments were repeated at least 3 times. The synergistic interaction formula for anticancer agents and the t-test were used for the analysis of the results. LND was shown to be effective when used in continuous exposure only (IC50 = 0.58). The IC50 of DDP was 1.1 and the IC50 of CARBO was 0.64. Significant dose related antiproliferative effect of LND alone, as well as DDP and CARBO cytotoxicity potentiation was observed (p<0.05). LND was shown to have synergistic effect when combined with platinum compounds to treat ovarian cancer cells at doses of 20 and 30 mu g/ml. These doses are achievable in patients. LND, a relatively new antineoplastic agent with good clinical tolerance, has been shown to synergistically potentiate the antiproliferative effect of platinum compounds on platinum resistant ovarian cancer cells. LND is an agent of potential use for the treatment of ovarian cancer patients in combination with DDP or CARBO.