Valproic acid inhibits proliferation and induces apoptosis in acute myeloid leukemia cells expressing P-gp and MRP1

Tang, Ruoping; Am, Faussat; Majdak, Patricia; Jy, Perrot; Chaoui, Driss; Legrand, Ollivier; Jp, Marie

doi:10.1038/sj.leu.2403390

Cited by 120 publications

(87 citation statements)

References 23 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…However, VPA had weaker effects than lithium. We supposed that SK-N-SH is a neuroblastoma cell, and it is known that VPA can induce apoptosis in several tumor cells (55)(56)(57). Additionally, we observed that Htt590-100Q (K444R) was more likely to localized in the nucleus when compared with Htt590-100Q in the SK-N-SH cells; however, there was no difference in the HeLa cells.…”

Section: Lithium-induced Down-regulation Of Hdac1 Is Essential For Thmentioning

confidence: 40%

Lithium Down-regulates Histone Deacetylase 1 (HDAC1) and Induces Degradation of Mutant Huntingtin

Zheng

Huang

et al. 2013

Journal of Biological Chemistry

View full text Add to dashboard Cite

Background: Lithium and valproic acid (VPA) exhibit a robust neuroprotective and anti-tumor effects in neural cells and tumor cells. Results: Lithium significantly down-regulates HDAC1 at the translational level by targeting HDAC1 mRNA. Conclusion:The decrease in HDAC1 is essential for the lithium-mediated, autophagic degradation of mutant huntingtin. Significance: This report is the first demonstration that HDAC1 decreases in response to lithium treatment.

show abstract

Section: Lithium-induced Down-regulation Of Hdac1 Is Essential For Thmentioning

confidence: 40%

Lithium Down-regulates Histone Deacetylase 1 (HDAC1) and Induces Degradation of Mutant Huntingtin

Zheng

Huang

et al. 2013

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…We and others have reported that chemical and genetic inhibition of HDACs leads to decreased expression of FLIP mRNA (36)(37)(38)(39)(40)(41)(42)(43). However, the mechanism by which inhibiting HDACs decreases FLIP expression is uncertain.…”

Section: Discussionmentioning

confidence: 99%

Selective Inhibition of Histone Deacetylases Sensitizes Malignant Cells to Death Receptor Ligands

Wood

Dalili

Simpson

et al. 2010

Molecular Cancer Therapeutics

View full text Add to dashboard Cite

Evasion of death receptor ligand-induced apoptosis represents an important contributor to cancer development and progression. Therefore, molecules that restore sensitivity to death receptor stimuli would be important tools to better understand this biological pathway and potential leads for therapeutic adjuncts. Previously, the small-molecule 4-(4-chloro-2-methylphenoxy)-N-hydroxybutanamide (that we propose be named droxinostat) was identified as a chemical sensitizer to death receptor stimuli, decreasing the expression of the caspase-8 inhibitor FLIP. However, the direct targets of droxinostat were unknown. To better understand the mechanism of action of droxinostat and highlight new strategies to restore sensitivity to death receptor ligands, we analyzed changes in gene expression using the Connectivity Map after treating cells with droxinostat. Changes in gene expression after droxinostat treatment resembled changes observed after treatment with histone deacetylase (HDAC) inhibitors. Therefore, we examined the effects of droxinostat on HDAC activity and showed that it selectively inhibited HDAC3, HDAC6, and HDAC8 and that inhibition of these HDACs was functionally important for its ability to sensitize cells to death ligands. Thus, we have identified a selective HDAC inhibitor and showed that selective HDAC inhibition sensitizes cells to death ligands, thereby highlighting a new mechanism to overcome resistance to death receptor ligands. Mol Cancer Ther; 9(1); 246-56. ©2010 AACR.

show abstract

“…Cytotoxicity assays were conducted with HL-60, a VPA-sensitive cell line, and varying VPA concentrations alone or in combination with a minimally cytotoxic gemcitabine concentration (10 nmol/L; ref. 33). VPA was cytotoxic at concentrations of 1 mmol/L and potentiated gemcitabine activity when present at 1,000-fold higher concentration (0.1 mmol/L; data not shown).…”

Section: Valproic Acidmentioning

confidence: 99%

Efficacy of Low-Dose Oral Metronomic Dosing of the Prodrug of Gemcitabine, LY2334737, in Human Tumor Xenografts

Pratt

Durland-Busbice

Shepard

et al. 2013

Molecular Cancer Therapeutics

View full text Add to dashboard Cite

LY2334737, an oral prodrug of gemcitabine, is cleaved in vivo, releasing gemcitabine and valproic acid. Oral dosing of mice results in absorption of intact prodrug with slow systemic hydrolysis yielding higher plasma levels of LY2334737 than gemcitabine and prolonged gemcitabine exposure. Antitumor activity was evaluated in human colon and lung tumor xenograft models. The dose response for efficacy was examined using 3 metronomic schedules, once-a-day dosing for 14 doses, every other day for 7 doses, and once a day for 7 doses, 7 days rest, followed by an additional 7 days of once-a-day dosing. These schedules gave significant antitumor activity and were well tolerated. Oral gavage of 6 mg/kg LY2334737 daily for 21 days gave equivalent activity to i.v. 240 mg/kg gemcitabine. HCl administered once a week for 3 weeks to mice bearing a patient mesothelioma tumor PXF 1118 or a non-small cell lung cancer tumor LXFE 937. The LXFE 397 tumor possessed elevated expression of the equilibrative nucleoside transporter-1 (ENT1) important for gemcitabine uptake but not prodrug uptake and responded significantly better to treatment with LY2334737 than gemcitabine (P 0.001). In 3 colon xenografts, antitumor activity of LY2334737 plus a maximally tolerated dose of capecitabine, an oral prodrug of 5-fluorouracil, was significantly greater than either monotherapy. During treatment, the expression of carboxylesterase 2 (CES2) and concentrative nucleoside transporter-3 was induced in HCT-116 tumors; both are needed for the activity of the prodrugs. Thus, metronomic oral low-dose LY2334737 is efficacious, well tolerated, and easily combined with capecitabine for improved efficacy. Elevated CES2 or ENT1 expression may enhance LY2334737 tumor response.

show abstract

Valproic acid inhibits proliferation and induces apoptosis in acute myeloid leukemia cells expressing P-gp and MRP1

Cited by 120 publications

References 23 publications

Lithium Down-regulates Histone Deacetylase 1 (HDAC1) and Induces Degradation of Mutant Huntingtin

Lithium Down-regulates Histone Deacetylase 1 (HDAC1) and Induces Degradation of Mutant Huntingtin

Selective Inhibition of Histone Deacetylases Sensitizes Malignant Cells to Death Receptor Ligands

Efficacy of Low-Dose Oral Metronomic Dosing of the Prodrug of Gemcitabine, LY2334737, in Human Tumor Xenografts

Contact Info

Product

Resources

About