Overcoming drug resistance in ovarian carcinoma

Fracasso, Paula M.

doi:10.1007/s11912-001-0038-z

Cited by 14 publications

(7 citation statements)

References 53 publications

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“…In fact, besides blocking activation, glutathione competes with cisplatin for cellular targets, enhances formation of platinum‐coordination complexes, as well as facilitates its efflux (Kartalou and Essigmann, 2001; Siddik, 2003). There has been evidence that associates glutathione with cisplatin resistance in ovarian cancer cells (Fracasso, 2001). The cell line C200, which has acquired resistance by in vitro exposure to cisplatin, has five‐fold higher gluthathione than the parental cells.…”

Section: Discussionmentioning

confidence: 99%

Epigallocatechin‐3‐gallate delivers hydrogen peroxide to induce death of ovarian cancer cells and enhances their cisplatin susceptibility

Chan

Soprano

Weinstein

et al. 2006

Journal Cellular Physiology

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The green tea polyphenol epigallocatechin-3-gallate (EGCG) has cancer chemopreventive properties against various types of cancers. The compound is known to attack various targets in transformed cells. In this report, we examined the action of EGCG on ovarian cancer cells. Eight ovarian cancer cell lines were tested (SKOV3, CAOV3, OVCAR3, OVCAR10, A2780, CP70, C30, and C200) and showed IC50s for EGCG at the micromolar range, including ones that are resistant to the chemotherapeutic drug cisplatin. The ovarian cancer cells were sensitive to H2O2 at similar concentrations, and EGCG treatment led to enhanced intracellular H2O2. Neutralization with pyruvate, a scavenger of H2O2, suggests that the toxicity of EGCG may be mediated by oxidative stress from the free radical. Addition of Tempol, a superoxide dismutase mimetic, demonstrates that H2O2 might be generated endogenously from superoxide. The toxicity of cisplatin and the development of cisplatin resistance are major obstacles in treatment of ovarian cancer. We found that addition of EGCG amplified the toxicity of cisplatin. EGCG increased cisplatin potency by three to six-fold in SKOV3, CAOV3, and C200 cells, the latter being a cell line induced to have several hundred fold resistant to cisplatin above the parental line. Our findings suggest that EGCG may accentuate oxidative stress to inhibit growth of ovarian cancer cells and sensitize them to cisplatin.

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Section: Discussionmentioning

confidence: 99%

Epigallocatechin‐3‐gallate delivers hydrogen peroxide to induce death of ovarian cancer cells and enhances their cisplatin susceptibility

Chan

Soprano

Weinstein

et al. 2006

Journal Cellular Physiology

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“…Ceramide has been shown to play a central role in both apoptotic and mitogenic pathways [2, 29–32]. Ceramide is generated in mass in response to various stressors including cytokines, radiation, and chemotherapy [33–36].…”

Section: Introductionmentioning

confidence: 99%

P-glycoprotein antagonists confer synergistic sensitivity to short-chain ceramide in human multidrug-resistant cancer cells

Chapman

Gouazé-Andersson

Karimi

et al. 2011

Experimental Cell Research

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P-glycoprotein (P-gp) antagonists inhibit ceramide metabolism at the juncture of glycosylation. The purpose of this study was to test whether targeting P-gp would be a viable alternative to targeting glucosylceramide synthase (GCS) for enhancing ceramide cytotoxicity. A2780 wild-type, and multidrug resistant 2780AD and NCI/ADR-RES human ovarian cancer cell lines and the cell-permeable ceramide analog, C6-ceramide (C6-cer), were employed. Compared to P-gp-poor A2780 cells, P-gp-rich 2780AD cells converted 3.7-fold more C6-cer to nontoxic C6-glucosylceramide (C6-GC), whereas cell-free GCS activities were equal. 2780AD cells displayed resistance to C6-cer (10 μM) that was reversed by inclusion of the P-gp antagonist tamoxifen (5 μM) but not by inclusion of a GCS inhibitor. Co-administration of C6-cer and P-gp antagonists was also effective in NCI/ADR-RES cells. For example, C6-cer, VX-710 (Biricodar), and cyclosporin A (cyc A) exposure resulted in viabilities of ~90% of control; however, C6-cer/VX-710 and C6-cer/cyc A additions were synergistic and resulted in viabilities of 22 and 17%, respectively. Further, whereas C6-ceramide and cyc A imparted 1.5- and zero-fold increases in caspase 3/7 activity, the combination produced a 3.5-fold increase. Although the upstream elements of cell death have not been elucidated, the novel C6-ceramide/P-gp antagonist combination merits further study and assessment of clinical translational potential.

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“…Tumor cell resistance to these drugs may involve reduced cellular accumulation, altered drug metabolism, altered DNA repair, and up-regulated cell survival pathways (2). In addition, the altered energy metabolism in tumor cells is now increasingly acknowledged as an important and general factor in drug resistance and, indeed, tumor progression (3)(4)(5).…”

Section: Introductionmentioning

confidence: 99%

Ovarian carcinoma cells with low levels of β-F1-ATPase are sensitive to combined platinum and 2-deoxy-d-glucose treatment

Hernlund

Hjerpe²,

Åvall‐Lundqvist³

et al. 2009

Molecular Cancer Therapeutics

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We have here examined chemopotentiating effects of glycolysis inhibitor 2-deoxy-D-glucose (DG) in two epithelial ovarian carcinoma (EOC) cell lines and 17 freshly isolated ascitic EOC cell samples, and we identify low expression of the β-F1-ATPase involved in mitochondrial ATP production as a candidate marker for sensitivity to this strategy. Although in the majority of samples, DG per se did not induce apoptosis, cotreatment with DG potentiated apoptosis and total antiproliferative effects of cisplatin and, to a lesser degree, carboplatin. In the cell lines, combination treatment with DG and cisplatin or carboplatin at noninhibitory concentrations prevented posttreatment regrowth in drug-free medium over a total of 5 days. DG per se allowed complete recuperation in drug-free medium. The more platinum-resistant a cell line was, the more sensitive it was to potentiation by DG and showed higher glucose uptake, DG-sensitive lactate production, and lower β-F1-ATPase levels. In the ascitic samples, DG reduced the median IC 50 for cisplatin by 68% and, in the most sensitive samples, up to 90%, and DG-mediated potentiation correlated with low expression of β-F1-ATPase. By contrast, cisplatin sensitivity did not correlate with β-F1-ATPase levels. The findings validate targeting cancer cell glucose metabolism for potentiating platinum chemotherapy in EOC and indicate that reduced β-F1-ATPase/oxidative phosphorylation distinguishes cells that are amenable to this strategy.

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Overcoming drug resistance in ovarian carcinoma

Cited by 14 publications

References 53 publications

Epigallocatechin‐3‐gallate delivers hydrogen peroxide to induce death of ovarian cancer cells and enhances their cisplatin susceptibility

Epigallocatechin‐3‐gallate delivers hydrogen peroxide to induce death of ovarian cancer cells and enhances their cisplatin susceptibility

P-glycoprotein antagonists confer synergistic sensitivity to short-chain ceramide in human multidrug-resistant cancer cells

Ovarian carcinoma cells with low levels of β-F1-ATPase are sensitive to combined platinum and 2-deoxy-d-glucose treatment

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