Histone deacetylase inhibitor, suberoylanilide hydroxamic acid (SAHA), enhances anti-tumor effects of the poly (ADP-ribose) polymerase (PARP) inhibitor olaparib in triple-negative breast cancer cells

Abstract

IntroductionOlaparib, a poly (ADP-ribose) polymerase (PARP) inhibitor, has been found to have therapeutic potential for treating cancers associated with impaired DNA repair capabilities, particularly those with deficiencies in the homologous recombination repair (HRR) pathway. Histone deacetylases (HDACs) are important for enabling functional HRR of DNA by regulating the expression of HRR-related genes and promoting the accurate assembly of HRR-directed sub-nuclear foci. Thus, HDAC inhibitors have recently emerged as a therapeutic agent for treating cancer by inhibiting DNA repair. Based on this, HDAC inhibition could be predicted to enhance the anti-tumor effect of PARP inhibitors in cancer cells by blocking the HRR pathway.MethodsWe determined whether suberoylanilide hydroxamic acid (SAHA), a HDAC inhibitor, could enhance the anti-tumor effects of olaparib on breast cancer cell lines using a cytotoxic assay, cell cycle analysis, and Western blotting. We evaluated how exposure to SAHA affects the expression of HRR-associated genes. The accumulation of DNA double strand breaks (DSBs) induced by combination treatment was assessed. Induction of autophagy was monitored by imaging green fluorescent protein-tagged microtubule-associated protein 1A/1B-light chain 3 (LC3) expression following co-treatment with olaparib and SAHA. These in vitro data were validated in vivo using a human breast cancer xenograft model.ResultsTriple-negative breast cancer cell (TNBC) lines showed heterogeneous responses to the PARP and HDAC inhibitors. Co-administration of olaparib and SAHA synergistically inhibited the growth of TNBC cells that expressed functional Phosphatase and tensin homolog (PTEN). This effect was associated with down-regulation of the proliferative signaling pathway, increased apoptotic and autophagic cell death, and accumulation of DNA damage. The combined anti-tumor effect of olaparib and SAHA was also observed in a xenograft model. These data suggest that PTEN expression in TNBC cells can sensitize the cell response to simultaneous inhibition of PARP and HDAC both in vitro and in vivo.ConclusionOur findings suggest that expression of functional PTEN may serve as a biomarker for selecting TNBC patients that would favorably respond to a combination of olaparib with SAHA. This provides a strong rationale for treating TNBC patients with PTEN expression with a combination therapy consisting of olaparib and SAHA.Electronic supplementary materialThe online version of this article (doi:10.1186/s13058-015-0534-y) contains supplementary material, which is available to authorized users.

Histone Deacetylases as New Therapeutic Targets in Triple-negative Breast Cancer: Progress and Promises

“…In the majority of the studies, co-treatment of an HDAC inhibitor with another compound induced the inhibition of tumor growth and showed anti-proliferative effects (46,47,77,84,115,123,138,154). Also, several HDAC inhibitors are assosiated not only with autophagic cell death, but also apoptosis (44,55,70,71,84,97,153).…”

“…An in vivo study of a MDA-MB-231 xenograft model confirmed this evidence. Moreover, this combination seemed to induce both apoptotic and autophagic cell death, thus enhanced the cytotoxic effects of these inhibitors (46). Further studies could examine more combined treatments of PARP inhibitors with other HDAC inhibitors in order to improve therapeutic approaches for TNBC patients.…”

Differences in Expression of Key DNA Damage Repair Genes after Epigenetic-Induced BRCAness Dictate Synthetic Lethality with PARP1 Inhibition

“…The cytotoxic activity of PARP inhibition relies upon unresolved ssDNA damage to create dsDNA breaks upon replication fork collapse and activation of apoptosis (2). Cell-cycle arrest stifles this mechanism and can, in part, provide an explanation for the lack of PARP activity, while loss of PTEN is thought to inhibit response (21). The observed G 1 arrest in response to ROMI in cells with reconstituted BRCA1 (Fig.…”

“…We observed that the MDA-MB-436 cells had reduced HR-mediated repair capacity and were generally less responsive to the combination therapy, which could be attributed to functional loss of BRCA1 (21). We wanted to validate these results using the HCC1937 breast cancer cell line.…”

“…This would suggest a possible mechanism for inhibition of ABT-888 activity, which requires active cycling cells for induced DNA damage (2). A recent study also attributed PTEN expression as a determinant for sensitivity to the combination of SAHA and PARPi (21). MDA-MB-231 has functional PTEN while MDA-MB-436 does not express the protein (22).…”