The histone deacetylase inhibitors (HDIs) have shown promise in the treatment of a number of hematologic malignancies, leading to the approval of vorinostat and romidepsin for the treatment of cutaneous T-cell lymphoma and romidepsin for the treatment of peripheral T-cell lymphoma by the U. S. Food and Drug Administration. Despite these promising results, clinical trials with the HDIs in solid tumors have not met with success. Examining mechanisms of resistance to HDIs may lead to strategies that increase their therapeutic potential in solid tumors. However, relatively few examples of drug-selected cell lines exist, and mechanisms of resistance have not been studied in depth. Very few clinical translational studies have evaluated resistance mechanisms. In the current review, we summarize many of the purported mechanisms of action of the HDIs in clinical trials and examine some of the emerging resistance mechanisms.

H-RasV12 oncogene has been shown to promote autophagic cell death. Here, we provide evidence of a contextual role for H-RasV12 in cell death that is varied by its effects on miR-130a. In E1A-immortalized murine embryo fibroblasts, acute expression of H-RasV12 promoted apoptosis, but not autophagic cell death. miRNA screens in this system showed that miR-130a was strongly downregulated by H-RasV12 in this model system. Enforced expression of miR-130a increased cell proliferation in part via repression of PTEN. Consistent with this effect, miR-130a overexpression in human breast cancer cells promoted Akt phosphorylation, cell survival, and tumor growth. In clinical specimens of multiple human cancers, expression of miR-130 family members correlated inversely with PTEN expression. Overall, our results defined miR-130a as an oncogenic miRNA that targets PTEN to drive malignant cell survival and tumor growth. .

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Purpose-ABCG2 overexpression has been linked to resistance to topoisomerase inhibitors, leading us to examine the potential interaction between ABCG2 and becatecarin.Methods-Interaction with ABCG2 was determined by ATPase assay, competition of [ 125 I] iodoarylazidoprazosin (IAAP) photolabeling and flow cytometry. Cellular resistance was measured in four-day cytotoxicity assays. ABCG2 expression was measured by fluorescent-substrate transport assays and immunoblot.Results-Becatecarin competed [ 125 I]-IAAP labeling of ABCG2, stimulated ATPase activity and, at concentrations greater than 10 μM, inhibited ABCG2-mediated transport. Becatecarin-selected A549 Bec150 lung carcinoma cells were 3.1-fold, 15-fold, 8-fold, and 6.8-fold resistant to becatecarin, mitoxantrone, SN-38 and topotecan, respectively. A549 Bec150 cells transported the ABCG2 substrates pheophorbide a, mitoxantrone and BODIPY-prazosin and displayed increased staining with the anti-ABCG2 antibody 5D3 compared to parental cells. Increased ABCG2 expression was confirmed by immunoblot.Conclusions-Our results suggest that becatecarin is transported by ABCG2 and can induce ABCG2 expression in cancer cells.