title: Overcoming chemotherapy resistance of ovarian cancer cells by liposomal cisplatin: molecular mechanisms unveiled by gene expression profiling.
abstract: Previously we reported that liposomal cisplatin (CDDP) overcomes CDDP resistance of ovarian A2780cis cancer cells (Krieger et al., Int. J. Pharm. 389, 2010, 10-17). Here we find that the cytotoxic activity of liposomal CDDP is not associated with detectable DNA platination in resistant ovarian cancer cells. This suggests that the mode of action of liposomal CDDP is different from the free drug. To gain insight into mechanisms of liposomal CDDP activity, we performed a transcriptome analysis of untreated A2780cis cells, and A2780cis cells in response to exposure with IC50 values of free or liposomal CDDP. A process network analysis of upregulated genes showed that liposomal CDDP induced a highly different gene expression profile in comparison to the free drug. p53 was identified as a key player directing transcriptional responses to free or liposomal CDDP. The free drug induced expression of essential genes of the intrinsic (mitochondrial) apoptosis pathway (BAX, BID, CASP9) most likely through p38MAPK activation. In contrast, liposomal CDDP induced expression of genes from DNA damage pathways and several genes of the extrinsic pathway of apoptosis (TNFRSF10B-DR5, CD70-TNFSF7). It thus appears that liposomal CDDP overcomes CDDP resistance by inducing DNA damage and in consequence programmed cell death by the extrinsic pathway. Predictions from gene expression data with respect to apoptosis activation were confirmed at the protein level by an apoptosis antibody array. This sheds new light on liposomal drug carrier approaches in cancer and suggests liposomal CDDP as promising strategy for the treatment of CDDP resistant ovarian carcinomas.
authors: Pharmaceutical Institute, Rheinische Friedrich Wilhelms University Bonn, An der Immenburg 4, 53121 Bonn, Germany.
authors: Martin
authors: M
authors: Koch
authors: Michaela L
authors: ML
authors: Krieger
authors: Daniel
authors: D
authors: Stölting
authors: Norbert
authors: N
authors: Brenner
authors: Manfred
authors: M
authors: Beier
authors: Ulrich
authors: U
authors: Jaehde
authors: Michael
authors: M
authors: Wiese
authors: Hans-Dieter
authors: HD
authors: Royer
authors: Gerd
authors: G
authors: Bendas
mesh_terms: D000970:Antineoplastic Agents / Q000008:administration & dosage*; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000008:administration & dosage* / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D008081:Liposomes; D010051:Ovarian Neoplasms / Q000188:drug therapy*; D016159:Tumor Suppressor Protein p53 / Q000502:physiology
chemical_list: D000970:Antineoplastic Agents; D006877:Hydroxamic Acids; D008081:Liposomes; D016159:Tumor Suppressor Protein p53; C012589:trichostatin A; D002945:Cisplatin