• 2018-07
  • 2019-04
  • 2019-05
  • 2019-06
  • 2019-07
  • 2019-08
  • 2019-09
  • 2019-10
  • 2019-11
  • 2019-12
  • 2020-01
  • 2020-02
  • 2020-03
  • 2020-04
  • 2020-05
  • 2020-06
  • 2020-07
  • 2020-08
  • 2020-09
  • 2020-10
  • 2020-11
  • 2020-12
  • 2021-01
  • 2021-02
  • 2021-03
  • 2021-04
  • 2021-05
  • 2021-06
  • 2021-07
  • 2021-08
  • 2021-09
  • 2021-10
  • 2021-11
  • 2021-12
  • Importantly HDACi mediated effects are cell and HDAC


    Importantly, HDACi-mediated effects are cell and HDAC specific; different effects and outcomes have been observed in different cell types, targeting different HDAC isoforms. While HDACi exhibit a strong proapoptotic potential in human leukemia Santacruzamate A 19, 20, 21, 22, they have a limited ability to induce apoptosis in solid cancer cells 23, 24, 25. In addition, whereas HDAC inhibition by vorinostat inhibits CXCL8 expression in CTCL Hut-78 cells, it increases CXCL8 expression in ovarian cancer (OC) cells 26, 27. Targeting class I HDACs induces IL-10 expression in macrophages, whereas HDAC6 suppression inhibits IL-10 production in macrophages 28, 29, 30. HDAC6 effectively deacetylates tubulin dimers, but the deacetylation rate of tubulin polymeric forms is much slower [31]. Identification of cellular targets of the individual HDACs and HDACi in different cell types is crucial for the development of targeted HDAC-based anticancer strategies.
    HDACi Have Anti-Inflammatory Effects in Stimulated Leukocytes, but Proinflammatory and Proangiogenic Effects in Solid Cancer Cells Even though HDACi were originally developed as anticancer drugs, based on their ability to induce apoptosis in hematopoietic malignancies, they also exhibit anti-inflammatory properties. In most immune cells, including monocytic cells, macrophages, and dendritic cells stimulated with lipopolysaccharide or TNF, HDACi suppress the expression of NFκB-dependent proinflammatory cytokines, including TNF, IL-1, and IL-6 32, 33, 34, 35, 36, 37. Intriguingly, however, in solid cancer cells characterized by constitutively increased NFκB activity, HDACi increase the expression of NFκB-dependent proinflammatory genes, and this is associated with the increased survival, proliferation, and migration of solid cancer cells (Table 1). In cervical cancer HeLa cells, inhibition of HDAC class I and II activity by trichostatin A (TSA) increased both basal and TNF-induced NFκB-dependent CXCL8 expression 38, 39. HDAC1 and HDAC2 were found to regulate NFκB transcriptional activity through a direct association of HDAC1 with the Rel homology domain of p65. While HDAC2 does not appear to interact with p65 directly, it can regulate NFκB activity through its association with HDAC1 [38]. CXCL8 expression, as well as that of the NFκB-dependent prosurvival gene cIAP1, was also induced in HeLa cells by apicidin, which preferentially inhibits HDAC class I [40]. Apicidin-induced CXCL8 and cIAP1 expression in HeLa cells was mediated by IKK, and associated with resistance to apicidin-induced apoptosis [40]. Inhibition of HDAC activity by pan-HDACi also failed to induce apoptosis in non-small cell lung cancer (NSCLC) cells, and this was associated with increased transactivation potential of p65, recruitment of the p300 transcriptional co-activator and histone acetyltransferase (HAT) to chromatin, and increased expression of CXCL8, Bcl-xL, and MMP9 23, 24. Interestingly, in addition to inducing expression of CXCL8 in NSCLC cells, TSA induced the expression of the CXCL8 receptors CXCR1 and CXCR2, which are also regulated by NFκB, while it suppressed expression of CXCL1, CXCL2, and CXCL3 [41]. Inhibition of class I HDACs by romidepsin also induced CXCL9 and CXCL10 expression in human lung cancer cells, mouse lung tumors, and tumor-infiltrating macrophages and T cells [16]. In human breast cancer cells, TSA induced IKK-dependent CXCL8 expression and release that were associated with increased histone H3 promoter acetylation and nuclear p65 accumulation [42]. In human OC cells, inhibitors of HDAC1, 2, and Santacruzamate A 3, CI994 and romidepsin, but not inhibitors of HDACs class II, specifically induced IKK-dependent CXCL8 expression that was associated with increased p65 promoter recruitment 26, 27. Suppression or neutralization of the CXCL8 induced by class I HDACi in OC cells increased their proapoptotic and antiproliferative effects 26, 27. CXCL8, originally discovered as a neutrophil chemoattractant and inducer of leukocyte-mediated inflammation, is a proinflammatory and proangiogenic chemokine that contributes to cancer progression through its induction of tumor cell proliferation, survival, and migration 43, 44, 45, 46. Increased production of CXCL8 confers a tremendous growth advantage to malignant cells, and increased CXCL8 levels correlate with poor prognosis in solid tumors, including OC, breast, lung, and prostate cancer 46, 47, 48, 49, 50, 51. Interestingly, recent studies have shown that HDACi also induce CXCL8 expression in cancer-associated fibroblasts (CAF) 52, 53. The HDACi-induced CXCL8 released by solid tumor cells and CAF then activates tumor-associated macrophages and neutrophils to release more CXCL8, which further amplifies the proangiogenic and metastatic effect (Figure 1). Since suppression of the HDACi-induced CXCL8 release potentiates the cytotoxic and proapoptotic effect of HDACi [26], these data indicate that targeting the HDACi-induced, IKK-dependent expression of CXCL8 and other proinflammatory chemokines may increase effectiveness of HDACi in OC and other solid tumors characterized by HDACi-induced chemokine expression.