Acquired resistance to SAHA is MDR-independent and correlates with losses of histone acetylation, cell cycle arrest and apoptosis

Histone deacetylase inhibitors (HDACi) such as SAHA (suberoylanilide hydroxamic acid) act epigenetically by regulating gene expression through chromatin remodeling. The antineoplastic activity of HDACi is an unquestionable property HDACi. But recent studies have revealed another aspect of HDACi: their association with drug resistance. In particular, resistance acquisition during chemotherapy is a frequent obstacle in cancer treatment. A stable 3-fold SAHA-resistant HCT116/SAHA subline was generated by stepwise exposures of the HCT116 colon tumor cell line to increasing concentrations of SAHA. The acquired SAHA resistance found with this subline is multidrug resistance transporter-independent, correlates with the loss of important molecular responses typically seen with HDACi, including losses of histone acetylation, cell cycle arrest, and apoptosis. It also associates with cross-resistance to other HDACi (trichostatin A, valproic acid) and to some “second-generation“ HDACi (LBH589). However, these HDACi-resistant cells retain responsiveness to “classic“ chemotherapeutics such as Docetaxel and Doxorubicin. Altered HDAC and HAT activities and increased expression of the reactive oxygen species-scavenger thioredoxin are not involved. This study provides evidence for the potential of SAHA to cause acquisition of HDACi resistance in colon tumor cells. A novel mechanism of SAHA-induced acquired resistance to HDACi is proposed, which differs from that reported for the HDACi depsipeptide. It is currently studied whether this mechanism operates also in gynecologic tumor cells.

Acquired resistance - Apoptosis - Histone deacetylaes inhibitors - SAHA