Valproic acid as epigenetic cancer drug: Preclinical, clinical and transcriptional effects on solid tumors

Dueñas‐González, Alfonso; Candelaria, Myrna; Pérez-Plascencia, Carlos; Pérez-Cárdenas, Enrique; Cruz-Hernández, Erick de la; Herrera, Luis A.

doi:10.1016/j.ctrv.2007.11.003

Cited by 313 publications

(257 citation statements)

References 111 publications

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“…As a pan-HDAC inhibitor, TSA targets both class I and class II HDACs, while VPA is known to be more specific toward class I HDACs (12)(13)(14). Interestingly, wild-type zebrafish embryos treated with TSA or VPA showed very similar phenotypes: in addition to ventrally curved body axis, they also showed lighter pigmentation (23) (Figs.…”

Section: Knockdown Of a Class I Hdac Gene Hdac1 Can Suppress Pkd2mentioning

confidence: 78%

“…To aid in the identification and quantification of the zebrafish body curvature phenotype, we developed a computer algorithm that can reliably classify individual animals among group pictures automatically, making it feasible to perform large-scale HTS for compound suppressors in the future. Significantly, as VPA is a class I HDACs inhibitor (12)(13)(14) and hdac1 encodes a class I HDAC, our results indicate that class I HDACs play a critical role in PKD pathogenesis and suggest that HDAC inhibitors may be excellent drug candidates for PKD treatment.…”

Section: Chemical Suppressor ͉ Zebrafishmentioning

confidence: 92%

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Chemical modifier screen identifies HDAC inhibitors as suppressors of PKD models

Cao¹,

Semanchik²,

Lee

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

177

156

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Polycystic kidney disease (PKD) is a common human genetic disease with severe medical consequences. Although it is appreciated that the cilium plays a central role in PKD, the underlying mechanism for PKD remains poorly understood and no effective treatment is available. In zebrafish, kidney cyst formation is closely associated with laterality defects and body curvature. To discover potential drug candidates and dissect signaling pathways that interact with ciliary signals, we performed a chemical modifier screen for the two phenotypes using zebrafish pkd2 hi4166 and ift172 hi2211 models. pkd2 is a causal gene for autosomal dominant PKD and ift172 is essential for building and maintaining the cilium. We identified trichostatin A (TSA), a pan-HDAC (histone deacetylase) inhibitor, as a compound that affected both body curvature and laterality. Further analysis verified that TSA inhibited cyst formation in pkd2 knockdown animals. Moreover, we demonstrated that inhibiting class I HDACs, either by valproic acid (VPA), a class I specific HDAC inhibitor structurally unrelated to TSA, or by knocking down hdac1, suppressed kidney cyst formation and body curvature caused by pkd2 deficiency. Finally, we show that VPA was able to reduce the progression of cyst formation and slow the decline of kidney function in a mouse ADPKD model. Together, these data suggest body curvature may be used as a surrogate marker for kidney cyst formation in large-scale high-throughput screens in zebrafish. More importantly, our results also reveal a critical role for HDACs in PKD pathogenesis and point to HDAC inhibitors as drug candidates for PKD treatment.

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Section: Knockdown Of a Class I Hdac Gene Hdac1 Can Suppress Pkd2mentioning

confidence: 78%

Section: Chemical Suppressor ͉ Zebrafishmentioning

confidence: 92%

Chemical modifier screen identifies HDAC inhibitors as suppressors of PKD models

Cao¹,

Semanchik²,

Lee

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

177

156

View full text Add to dashboard Cite

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“…SAHA (Vorinostat) is a currently approved agent against cutaneous T-cell lymphoma, and clinical trials are ongoing against breast cancer and other solid tumors or hematological malignancies [17,64]. Valproate was used primarily as an anticonvulsant and mood-stabilizing drug, but now, mostly in combination with other therapeutic agents, it is being tested in clinical studies for cancer treatment [17,65].…”

Section: Discussionmentioning

confidence: 99%

Histone deacetylase inhibitor- and PMA-induced upregulation of PMCA4b enhances Ca2+ clearance from MCF-7 breast cancer cells

et al. 2014

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The expression of the plasma membrane Ca 2+ ATPase (PMCA) isoforms is altered in several types of cancer cells suggesting that they are involved in cancer progression. In this study we induced differentiation of MCF-7 breast cancer cells by histone deacetylase inhibitors (HDACis) such as short chain fatty acids (SCFAs) or suberoylanilide hydroxamic acid (SAHA), and by phorbol 12-myristate 13-acetate (PMA) and found strong upregulation of PMCA4b protein expression in response to these treatments. Furthermore, combination of HDACis with PMA augmented cell differentiation and further enhanced PMCA4b expression both at mRNA and protein levels. Immunocytochemical analysis revealed that the upregulated protein was located mostly in the plasma membrane. To examine the functional consequences of elevated PMCA4b expression, the characteristics of intracellular Ca 2+ signals were investigated before and after differentiation inducing treatments, and also in cells overexpressing PMCA4b. The increased PMCA4b expression -either by treatment or overexpression -led to enhanced Ca 2+ clearance from the stimulated cells. We found pronounced PMCA4 protein expression in normal breast tissue samples highlighting the importance of this pump for the maintenance of mammary epithelial Ca 2+ homeostasis. These results suggest that modulation of Ca 2+ signaling by enhanced PMCA4b expression may contribute to normal development of breast epithelium and may be lost in cancer.3

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“…VPA is currently being tested alone or in combination with other agents mostly in hematological malignancies, 24 but there is increasing interest in testing on solid tumors. 23,25,36,39 Resistance to chemotherapy is a major problem in leukemia treatment, and despite the efficiency of fludarabine in the induction of clinical responses in CLL, resistance to this drug has been well documented. 40,41 Furthermore, new drugs in clinical trials with powerful apoptotic potential (for example, flavopiridol) can cause many side effects such as anemia, thrombocytopenia, infections, diarrhea and fatigue.…”

Section: Gene Expression Profile Of Vpa-treated Cll B Cells B Stamatomentioning

confidence: 99%

Antileukemic activity of valproic acid in chronic lymphocytic leukemia B cells defined by microarray analysis

et al. 2009

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Valproic acid as epigenetic cancer drug: Preclinical, clinical and transcriptional effects on solid tumors

Cited by 313 publications

References 111 publications

Chemical modifier screen identifies HDAC inhibitors as suppressors of PKD models

Chemical modifier screen identifies HDAC inhibitors as suppressors of PKD models

Histone deacetylase inhibitor- and PMA-induced upregulation of PMCA4b enhances Ca2+ clearance from MCF-7 breast cancer cells

Antileukemic activity of valproic acid in chronic lymphocytic leukemia B cells defined by microarray analysis

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