Hydroxychloroquine, chloroquine, and all-trans retinoic acid regulate growth, survival, and histone acetylation in breast cancer cells

Abstract

The antimalarial drugs chloroquine (CQ) and hydroxychloroquine (HCQ) have potential applications in cancer treatment. The growth of MCF-7 and MDA-MB-231 human breast cancer cells in vitro was inhibited by CQ and HCQ and these cells were more sensitive than nontumorigenic MCF-10A breast epithelial cells. Furthermore, all-trans retinoic acid (ATRA) augmented the anticancer effects of CQ and HCQ as evidenced by significant reductions in Ki67-positive cancer cells and clonogenicity compared with cells treated with CQ or HCQ in the absence of ATRA. As an earlier study suggested that CQ, HCQ, and ATRA are breast cancer cell differentiation agents, these agents were screened in cell-free histone deacetylase (HDAC) and histone acetyltransferase (HAT) assays. ATRA, but not CQ or HCQ, inhibited HDAC activity in HeLa nuclear extracts. Growth inhibitory concentrations of HCQ and ATRA stimulated purified p300/CBP-associated factor, where CBP is the cAMP-response element binding protein, HAT activity. To investigate whether growth inhibitory concentrations of these agents influenced protein acetylation in cells, gel-purified histone H3 and histone H4 were analyzed using mass spectrometry. HCQ alone and HCQ+ATRA treatments altered the acetylation status in the N-terminal lysines of histones H3 and H4 compared with dimethyl sulfoxide (DMSO) controls. The results indicated that HCQ and ATRA regulate protein acetylation events in MCF-7 breast cancer cells, and identify a potential mechanism for their effects on breast cancer cell growth and differentiation.

Autophagy and cell death signaling following dietary sulforaphane act independently of each other and require oxidative stress in pancreatic cancer

“…In combination with standard chemotherapy, CQ has been reported to enhance anti-cancer therapy efficiency in different cancer cell types (31,32). However, CQ treatment alone has been shown to induce apoptosis in several malignancies, indicating that CQ itself induces apoptotic cell death in cancer cells (31,33,34). In our experimental settings, CQ treatment did not influence SFN-induced cell death.…”

Histone acetyltransferase p300 promotes MRTF-A-mediates transactivation of VE-cadherin gene in human umbilical vein endothelial cells

“…Histone acetylation has emerged as a key player in the activation of genes at the beginning of transcription (Bourguignon et al, 2009;Rahim and Strobl, 2009). Histone acetyltransferase (HAT) p300 and CREBbinding protein have been widely reported and characterized.…”

Autophagy modulation as a target for anticancer drug discovery

“…For example, in colon cancer cells, the anticancer effects of 5-FU were augmented by combined treatment with CQ [109] . However, a recent study has reported that the enhancement of chemotherapy efficiency by CQ might be independent of autophagy [110] , which warrants caution for future investigations targeting the roles of CQ in combined cancer therapy [111] . Currently, many phase I/II clinical trials are ongoing to evaluate CQ-and HCQ-mediated modulation of autophagy in combination with standard treatment in patients with breast, colorectal, hematologic, kidney, lung, ovarian, pancreatic and prostate cancers ( Table 2).…”