Histone deacetylase inhibitor trichostatin A and autophagy inhibitor chloroquine synergistically exert anti-tumor activity in H-ras transformed breast epithelial cells

Abstract

Histone deacetylase inhibitors (HDACIs) cause oncogene-transformed mammalian cell death. Our previous study indicated that HDACIs activate forkhead box O1 (FOXO1) and induce autophagy in liver and colon cancer cells. However, whether FOXO1 is involved in HDACI-mediated oncogene-transformed mammalian cell death remains unclear. In the present study, H-ras transformed MCF10A cells were used to investigate the role of FOXO1 in this pathway. Results showed that trichostatin A (TSA), a HDACI, activated apoptosis in MCF10A-ras cells, but not in MCF10A cells. Furthermore, TSA activated FOXO1 via P21 upregulation, whereas the knockdown of FOXO1 reduced TSA-induced cell death. In addition, TSA induced autophagy in MCF10A and MCF10A-ras cells by blocking the mammailian target of rapamycin signaling pathway. Furthermore, autophagy inhibition lead to higher MCF10A-ras cell death by TSA, thus indicating that autophagy is essential in cell survival. Taken together, the present study demonstrated that TSA causes oncogene-transformed cell apoptosis via activation of FOXO1 and HDACI-mediated autophagy induction, which served as important cell survival mechanisms. Notably, the present findings imply that a combination of HDACIs and autophagy inhibitors produce a synergistic anticancer effect.

Synergistic effect of Chloroquine and Panobinostat in ovarian cancer through induction of DNA damage and inhibition of DNA repair

“…It had been previously described that the use of autophagy inhibitors, such as CQ, with drugs that induces autophagy, such as HDACi, enhanced the cytotoxic response of these drugs [ [18] , [19] , [20] , [21] , [22] , [23] , 48 ]. Therefore, we hypothesized that the synergistic effect obtained after CQ/LBH cotreatment could also be due, at least in part, to an inhibition of the prosurvival autophagy pathway.…”

“…HDACi also promote autophagy, but this effect instead of exerting antitumor effects has been proposed as a potential mechanism of resistance to these drugs; autophagy might recycle proteins to generate energy in an attempt to survive stressful conditions generated by the treatment [17] . This is the reason why some researchers have analyzed the effect of the combination of HDACi and other proautophagy drugs with autophagy inhibitors, such as Chloroquine (CQ), and have found synergistic effects in some tumor cell lines, such as breast, colon, leukemic and neuroblastoma cell lines [18] , [19] , [20] , [21] , [22] , [23] .…”

Cytoplasmic APE1 promotes lung cancer aggressiveness and cisplatin resistance via the COX-2/Akt/β-catenin signaling pathway

“…The current data suggest a model in which unmodi ed, full-length APE1 is mainly targeted to the nucleus via its N-terminal elements [3]. More importantly, APE1 is widely overexpressed in most tumor tissues, and APE1 overexpression is associated with poor prognosis, chemoresistance or radioresistance, and increased angiogenesis [4][5][6]. In this study, cytoplasmic APE1 may mediate resistance to cisplatin in lung cancer, and upregulation of cytoplasmic APE1 induced by plasmid transfection increased resistance to cisplatin.…”

Induction of STK11-dependent cytoprotective autophagy in breast cancer cells upon honokiol treatment

“…Our data showed that breast cancer cells undergo cytoprotective autophagy in response to HNK treatment suggesting that combining HNK with an autophagy inhibitor can potentially yield increased inhibition of breast tumor growth. Autophagy inhibitor, chloroquine has been shown to increase drug efficacy in preclinical studies 39,40 . We first determined whether the interaction between HNK and CQ is additive, synergistic or antagonistic in nature using Compusyn software (Compusyn Inc., Paramus, NJ, USA).…”