Potentiation of the anticancer effect of valproic acid, an antiepileptic agent with histone deacetylase inhibitory activity, by the kinase inhibitor Staurosporine or its clinically relevant analogue UCN-01

Yeow, Wen-Shuz; Ziauddin, M. Firdos; Maxhimer, Justin B.; Shamimi-Noori, Susan; Baras, Aris; Chua, Alex; Schrump, David S.; Nguyen, Dao M.

doi:10.1038/sj.bjc.6603132

Cited by 39 publications

(25 citation statements)

References 39 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…DNA methylation and histone deacetylase inhibitors exert antitumor effects by inhibiting cell proliferation, metastases, angiogenesis, and by inducing cell differentiation and/or apoptosis, as well as by increasing chemotherapy cytotoxicity (2)(3)(4)(5)(6). Nevertheless, chromatin remodeling agents also show promise for immune therapy of cancer.…”

Section: Introductionmentioning

confidence: 99%

Upregulation of NKG2D ligands and enhanced natural killer cell cytotoxicity by hydralazine and valproate

Chávez‐Blanco

Cruz-Hernández²,

Domínguez³

et al. 2011

Int J Oncol

View full text Add to dashboard Cite

Abstract. Natural killer cells play a role in the immune antitumor response by recognizing and eliminating tumor cells through the engagement of NKG2D receptors with their ligands on target cells. This work aimed to investigate whether epigenetic drugs are able to increase MICA and MICB expression as well as NK cell cytotoxicity. Prostate, colon, breast and cervical cancer cell lines were analyzed for the expression of MICA and MICB at the mRNA and protein levels by RT-PCR, Western blot, flow cytometry and ELISA. The activating mark H3K4m2 at the MICA and MICB promoters was investigated by ChIP assays. Cytotoxicity of NK cells against the target epithelial cancer cells was investigated with the CD107 cytotoxicity assay. The results show that hydralazine and valproic acid not only increase the expression of MICA and MICB ligands of target cells, but also reduce their shedding to the supernatant. This upregulation occurs at the transcriptional level as revealed by increase of the H3K4 activating mark at the promoter of MICA and MICB genes. These effects are paralleled by increased cytotoxicity of NK cells, which was attenuated at different degrees by using blocking antibodies against the NKG2D receptor and ligands. In conclusion, our results demonstrate the ability of hydralazine and valproate to increase the NK activity against epithelial cancer cell lines and suggest that these drugs could reduce the levels of soluble MICA and MICB helping in avoiding tumor-induced suppression of NK cytotoxicity against the tumor.

show abstract

Section: Introductionmentioning

confidence: 99%

Upregulation of NKG2D ligands and enhanced natural killer cell cytotoxicity by hydralazine and valproate

Chávez‐Blanco

Cruz-Hernández²,

Domínguez³

et al. 2011

Int J Oncol

View full text Add to dashboard Cite

show abstract

“…These observations lead to the development of several therapeutic approaches on the basis of histone deacetylase inhibitors. 11,12 The overall nonspecific nature of HDAC (histone deacetylases) inhibitors and its undesired effect on global gene expression inspired us to look for HAT activators. However, very few small molecule modulators of histone acetyltransferases are known so far.…”

Section: Introductionmentioning

confidence: 99%

Activation of p300 Histone Acetyltransferase by Small Molecules Altering Enzyme Structure: Probed by Surface-Enhanced Raman Spectroscopy

et al. 2007

View full text Add to dashboard Cite

Reversible acetylation of nucleosomal histones and nonhistone proteins play pivotal roles in the regulation of all the DNA templated phenomenon. Dysfunction of the enzymes involved in the acetylation/deacetylation leads to several diseases. Therefore, these enzymes are the targets for new generation therapeutics. Here, we report the synthesis of trifluoromethyl phenyl benzamides and their effect on histone acetyltransferase (HAT) activity of p300. One of these benzamides, CTPB (N-(4-chloro-3-trifluoromethyl-phenyl)-2-ethoxy-6-pentadecyl-benzamide), was discovered as a potent activator of the p300 HAT activity. We have found that pentadecyl hydrocarbon chain of CTPB is required to activate the HAT only under certain context. Furthermore, our results show that the relative position of -CF 3 and -Cl in CTB (N-(4-chloro-3-trifluoromethyl-phenyl)-2-ethoxy-benzamide) is also very critical for the activation. Surface-enhanced Raman spectroscopy (SERS) of p300 and the HAT activator complexes evidently suggest that the activation of HAT activity is achieved by the alteration of p300 structure. Therefore, apart from elucidating the chemical basis for small molecule mediated activation of p300, this report also describes, for the first time, Raman spectroscopic analysis of the complexes of histone-modifying enzymes and their modulators, which may be highly useful for therapeutic applications.

show abstract

“…Modulation of cell death pathways is being explored to fight against cancer (57) and fungal infections (3), and the development of drugs that target relevant metabolic pathways can increase the effects of death inducers. For instance, staurosporine and its clinically relevant analogue 7-hydroxystaurosporine (UCN-01) were recently found to increase the anticancer activity of valproic acid (63). Thus, the use of drug combinations, like staurosporine and rotenone, as antifungal and/or antitumor agents is likely to have an impact in the medical field.…”

mentioning

confidence: 99%

“…Drugs like staurosporine (STS), an inhibitor of protein kinases, have been used to induce the mitochondrion-dependent pathway of apoptosis (24,35). Staurosporine (48) and derivatives have been used in clinical trials for cancer therapy (63). The complex I inhibitor rotenone too has been widely used to induce PCD and also extensively applied as a pesticide (11,39,56).…”

mentioning

confidence: 99%

Rotenone Enhances the Antifungal Properties of Staurosporine

et al. 2010

View full text Add to dashboard Cite

We studied staurosporine-induced cell death in the filamentous fungus Neurospora crassa. The generation of reactive oxygen species during the process appears to be an important signaling event, since addition of the antioxidant glutathione prevents the effects of staurosporine on fungal growth. Selected mutants with mutations in respiratory chain complex I are extremely sensitive to the drug, stressing the involvement of complex I in programmed cell death. Following this finding, we determined that the complex I-specific inhibitor rotenone used in combination with staurosporine results in a synergistic and specific antifungal activity, likely through a concerted action on intracellular glutathione depletion. Paradoxically, the synergistic antifungal activity of rotenone and staurosporine is observed in N. crassa complex I mutants and in Saccharomyces cerevisiae, which lacks complex I. In addition, it is not observed when other complex I inhibitors are used instead of rotenone. These results indicate that the rotenone effect is independent of complex I inhibition. The combination of rotenone and staurosporine is effective against N. crassa as well as against the common pathogens Aspergillus fumigatus and Candida albicans, pointing to its usefulness as an antifungal agent.Programmed cell death (PCD) refers to a genetically controlled process of cellular suicide initiated by endogenous or extrinsic signals. Many of the genes involved are widely conserved from unicellular to multicellular organisms (46). Apoptosis and autophagy, with its particular characteristics, have been recognized as the main categories of PCD (27). The process of PCD is crucial for the development and homeostasis of metazoan organisms and has been implicated in a number of human disorders, including cancer and neurodegenerative and infectious diseases (3,10,25,55).The participation in PCD of mitochondria, the cellular organelles responsible for the production of most cellular ATP in eukaryotes (30), has been well established. Particularly, these organelles have a central role in the intrinsic (mitochondriondependent) pathway of apoptosis, which includes production of reactive oxygen species (ROS), membrane depolarization, ultrastructural changes, and the release of cytochrome c and other proteins (18,50,55). Drugs like staurosporine (STS), an inhibitor of protein kinases, have been used to induce the mitochondrion-dependent pathway of apoptosis (24, 35). Staurosporine (48) and derivatives have been used in clinical trials for cancer therapy (63). The complex I inhibitor rotenone too has been widely used to induce PCD and also extensively applied as a pesticide (11,39,56). Thus, these types of drugs can be employed for the acquisition of fundamental knowledge and for more practical applications, like modulation of the progression of PCD.Modulation of PCD by targeting metabolic pathways involved in the process can be exploited to the benefit of human health in several very significant situations, from cancer therapy (4, 57) to the treatment of f...

show abstract

Potentiation of the anticancer effect of valproic acid, an antiepileptic agent with histone deacetylase inhibitory activity, by the kinase inhibitor Staurosporine or its clinically relevant analogue UCN-01

Cited by 39 publications

References 39 publications

Upregulation of NKG2D ligands and enhanced natural killer cell cytotoxicity by hydralazine and valproate

Upregulation of NKG2D ligands and enhanced natural killer cell cytotoxicity by hydralazine and valproate

Activation of p300 Histone Acetyltransferase by Small Molecules Altering Enzyme Structure: Probed by Surface-Enhanced Raman Spectroscopy

Rotenone Enhances the Antifungal Properties of Staurosporine

Contact Info

Product

Resources

About