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Ovarian cancer cisplatin-resistant cell lines: multiple changes including collateral sensitivity to Taxol
P Perego1, S Romanelli, N Carenini
1Oncologia Sperimentale B, Istituto Nazionale per lo Studio e la Cura dei Tumori, Milan, Italy. perego@istitutotumori.mi.it
Summary
Ovarian cancer cells with p53 mutations develop cisplatin resistance through multiple defense mechanisms. Interestingly, these resistant cells show increased sensitivity to Taxol, suggesting its potential for treating p53-mutated tumors.
Area of Science:
- Molecular biology
- Cancer research
- Pharmacology
Background:
- Acquired resistance to cisplatin in ovarian carcinoma is often linked to alterations in apoptosis pathways, particularly p53 gene mutations.
- Cisplatin resistance is a complex, multifactorial phenomenon requiring a deeper understanding of associated molecular changes to optimize therapeutic strategies.
Purpose of the Study:
- To investigate the molecular mechanisms underlying cisplatin resistance in ovarian carcinoma.
- To compare cisplatin-resistant sublines with varying resistance levels regarding apoptosis, glutathione system, pharmacokinetics, and DNA damage.
- To evaluate the cross-resistance patterns and collateral sensitivity to other chemotherapeutic agents.
Main Methods:
- Development of two cisplatin-resistant ovarian carcinoma sublines (IGROV-1/Pt0.5 and IGROV-1/Pt1) with mutant p53.
- Assessment of cross-resistance to DNA-damaging agents and collateral sensitivity to Taxol.
- Analysis of apoptosis induction, intracellular glutathione levels, glutathione S-transferase, gamma-glutamyl transpeptidase activity, and metallothionein IIa expression.
- Evaluation of cellular pharmacokinetics and drug-induced DNA damage, including DNA platination.
Main Results:
- Resistant cells exhibited cross-resistance to DNA-damaging agents but showed collateral sensitivity to Taxol, with Taxol's efficacy correlating with apoptosis induction.
- Intracellular glutathione levels were elevated in resistant cells, while glutathione S-transferase and gamma-glutamyl transpeptidase levels were reduced, indicating complex regulation of glutathione.
- Reduced cisplatin-induced DNA cross-linking and a slight decrease in DNA-bound platinum were observed in resistant cells, suggesting a protective role for glutathione. Metallothionein IIa expression was increased.
Conclusions:
- Acquired cisplatin resistance in ovarian carcinoma involves multiple alterations, including reduced apoptosis susceptibility due to p53 inactivation and activation of defense mechanisms.
- The glutathione-dependent system plays a role in high-degree resistance, while Taxol's effectiveness in inducing apoptosis in p53-mutated cells highlights a p53-independent pathway.
- These findings suggest Taxol holds pharmacological interest for treating p53-mutated ovarian tumors that are resistant to cisplatin.