The Synergistic Effect of SAHA and Parthenolide in MDA‐MB231 Breast Cancer Cells

Abstract

The sesquiterpene lactone Parthenolide (PN) exerted a cytotoxic effect on MDA-MB231 cells, a triple-negative breast cancer (TNBC) cell line, but its effectiveness was scarce when employed at low doses. This represents an obstacle for a therapeutic utilization of PN. In order to overcome this difficulty we associated to PN the suberoylanilide hydroxamic acid (SAHA), an histone deacetylase inhibitor. Our results show that SAHA synergistically sensitized MDA-MB231 cells to the cytotoxic effect of PN. It is noteworthy that treatment with PN alone stimulated the survival pathway Akt/mTOR and the consequent nuclear translocation of Nrf2, while treatment with SAHA alone induced autophagic activity. However, when the cells were treated with SAHA/PN combination, SAHA suppressed PN effect on Akt/mTOR/Nrf2 pathway, while PN reduced the prosurvival autophagic activity of SAHA. In addition SAHA/PN combination induced GSH depletion, fall in Dcm, release of cytochrome c, activation of caspase 3 and apoptosis. Finally we demonstrated that combined treatment maintained both hyperacetylation of histones H3 and H4 induced by SAHA and down-regulation of DNMT1 expression induced by PN. Inhibition of the DNA-binding activity of NF-kB, which is determined by PN, was also observed after combined treatment. In conclusion, combination of PN to SAHA inhibits the cytoprotective responses induced by the single compounds, but does not alter the mechanisms leading to the cytotoxic effects. Taken together our results suggest that this combination could be a candidate for TNBC therapy.

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

“…They claimed that pre-treatment of MDA-MB231 cells with SAHA sensitized the cells to the cytotoxic effect of PN (62), so PN and SAHA acted synergistically in order to fight against TNBC cells (55). Moreover, they demonstrated that SAHA treatment leads to acetylation of lysine residues in the NH 2 -terminal tails of histones H3 and H4 and these findings were in accordance to other studies (63,64).…”

“…Finally, it has been found that SAHA and PN combined therapy induced a decrease of the expression levels of beclin-1, a protein involved in autophagosome formation (55). Previous studies have shown that beclin-1 is cleaved by caspases (67).…”

“…Carlisi et al studied the combination of SAHA and parthenolide (PN) (55). The principal bioactive sesquiterpene lactone component of feverfew Tanacetum parthenium, PN, was found to induce tumor inhibition on many cancer types, such as osteosarcoma, melanoma (56) and prostatic (57), pancreatic (58), colorectal (59) cancers.…”

“…PN acts cytotoxically on MDA-MB231 cells, but at low doses it is not effective (60,61). Investigators have combined PN and SAHA in order to overcome the PN's deficiency (55).…”

“…Both ROS generation and autophagy are reduced by two NADPH oxidase family (NOX) inhibitors -Nox enzymes are major ROS producers-, apocynin and diphenyleneiodonium chloride (DPI). Therefore, it was proposed that SAHA primarily induced NOX to increase the production of ROS, which led to activation of autophagy (55). Another study has shown that SAHA stimulates autophagy in tumor cells (66).…”