Abstract
Ovarian cancer is the fifth leading cause of cancer deaths. Chemoresistance, particularly against platinum compounds, contributes to a poor prognosis. Histone deacetylase inhibitors (HDACi) and heat shock protein 90 inhibitors (HSP90i) are known to modulate pathways involved in chemoresistance. This study investigated the effects of HDACi (panobinostat, LMK235) and HSP90i (luminespib, HSP990) on the potency of cisplatin in ovarian cancer cell lines (A2780, CaOV3, OVCAR3 and cisplatin-resistant sub-clones). Preincubation with HDACi increased the cytotoxic potency of HSP90i, whereas preincubation with HSP90i had no effect. Preincubation with HSP90i or HDACi 48h prior to cisplatin enhanced the cisplatin potency significantly in all cell lines via apoptosis induction and affected the expression of apoptosis-relevant genes and proteins. For CaOV3CisR and A2780CisR, a preincubation with HDACi for 48–72 h led to complete reversal of cisplatin resistance. Furthermore, permanent presence of HDACi in sub-cytotoxic concentrations prevented the development of cisplatin resistance in A2780. However, triple combinations of HDACi, HSP90i and cisplatin were not superior to dual combinations. Overall, priming with HDACi sensitizes ovarian cancer cells to treatment with HSP90i or cisplatin and has an influence on the development of cisplatin resistance, both of which may contribute to an improved ovarian cancer treatment.
Highlights
Ovarian cancer is among the five most deadly types of cancer in women [1]
In 2007, Solár et al reported that geldanamycin, one of the first discovered Heat shock protein 90 (HSP90) inhibitors (HSP90i), increased the sensitivity to cisplatin of the cisplatin-resistant ovarian cancer cell line A2780CisR [40]
Weberpals et al could show that the increase in cisplatin sensitivity by Histone deacetylase inhibitors (HDACi) could be caused by a decrease in the expression of BRCA1 [43]
Summary
Ovarian cancer is among the five most deadly types of cancer in women [1]. therapeutic options have improved in the last decades, the five-year survival rate remains at around 48% for ovarian cancer in the USA [2] and 40–43% in Germany [3,4]. A major obstacle of this therapy is the development of resistance against platinum-based drugs eventually leading to death. Many HSP90 client proteins such as Akt, MEK, receptor tyrosine kinases or estrogen receptors are members of proliferative and antiapoptotic pathways activated in drug-resistant ovarian cancers [16]. HSP90i are widely tested in different cancers such as colon, melanoma, prostate or ovarian cancer as single drug or as part of combination therapies [19,20,21,22,23,24]. Our group has previously shown that increased expression and phosphorylation of the HSP90 clients IGFR, ErbB2, and ErbB3 play a pivotal role in the development of resistance in ovarian cancer [25,26].
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