Valproic acid induces apoptosis in human leukemia cells by stimulating both caspase-dependent and -independent apoptotic signaling pathways

Kawagoe, Rika; Kawagoe, Hiroyuki; Sano, Kimihiko

doi:10.1016/s0145-2126(01)00151-5

Cited by 113 publications

(94 citation statements)

References 27 publications

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“…This extends previous reports of VPA-induced apoptosis in human leukemic cells lines. 26 In conclusion, we demonstrate in this paper that VPA, through inhibition of histone deacetylases, induces changes in gene expression and enhances the responsiveness of AML cells to ATRA. During the review of this paper, Kuedgen et al 27 published on the clinical improvement in 44% of patients treated with ATRA þ VPA.…”

Section: Discussionmentioning

confidence: 51%

The histone deacetylase inhibitor valproic acid alters sensitivity towards all trans retinoic acid in acute myeloblastic leukemia cells

et al. 2005

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Section: Discussionmentioning

confidence: 51%

The histone deacetylase inhibitor valproic acid alters sensitivity towards all trans retinoic acid in acute myeloblastic leukemia cells

et al. 2005

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“…VPA is well tolerated by patients and has been shown to have a marked HDAC inhibitor effect at the pharmaceutical level, inducing differentiation and apoptosis of transformed cells. 11,12 In this paper, we show that VPA is not a substrate of P-gp and MRP1, and that it does not modify their expression. We also show that VPA can induce cell cycle arrest and apoptosis in both Pgp-positive and -negative leukemia cells from cell lines and AML samples.…”

Section: Introductionmentioning

confidence: 60%

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

et al. 2004

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The multidrug resistance (MDR) phenotype, induced by the overexpression of several ABC transporters or by antiapoptotic mechanisms, has been identified as the major cause of drug resistance in the treatment of patients with acute myeloid leukemia (AML). In this study, we have shown that valproic acid (VPA) (a histone deacetylase inhibitor) can inhibit the proliferation of both P-glycoprotein (P-gp)-and MDR-associated protein 1 (MRP1)-positive and -negative cells. VPA also induced apoptosis of P-gp-positive cells. VPA induced apoptosis in K562 cells led to decrease in Flip (FLICE/caspase-8 inhibitory protein) expression with Flip cleavage, which could not be observed in HL60 cells. In HL60/MRP cell line, which proved to be resistant to apoptosis by VPA, we observed an abnormal expression of apoptotic regulatory proteins, overexpression of Bcl-2 and absence of Bax. Also, the Bcl-2 antagonist HA14-1 rapidly restored apoptosis in this cell line. Cotreatment with cytosine arabinoside induced very strong apoptosis in both K562/DOX and HL60/DNR cell lines. VPA also induced apoptosis in AML patient cells expressing P-gp and/or MRP1. Our findings show VPA as an interesting drug that should be tested in clinical trials for overcoming the MDR phenotype in AML patients.

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“…This finding suggests that normal hematopoiesis temporarily gained dominance over the residual leukemic clone. As VPA is known to induce differentiation as well as apoptosis in leukemic cell lines in vitro, 11,20 we examined whether leukemic cells differentiated into mature granulocytes by using FISH analysis of enriched CD34 ϩ BM cells and PB granulocytes. Strikingly, at the time of hematologic response, the i(17)(q10) was detected in 20% of the CD34 ϩ stem and progenitor cells but in none of the mature granulocytes.…”

Section: Response and Outcomementioning

confidence: 99%

Clinical trial of valproic acid and all‐trans retinoic acid in patients with poor‐risk acute myeloid leukemia

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Waßmann

et al. 2005

Cancer

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BACKGROUND Valproic acid (VPA), a histone deacetylase (HDAC) inhibitor, induced in vitro differentiation of primary acute myeloid leukemia (AML) blasts, an effect enhanced by all‐trans retinoic acid (ATRA). Clinical responses to VPA were recently observed in patients with myelodysplastic syndrome (MDS). Herein, the authors have described results of a clinical trial with VPA plus ATRA in 26 patients with poor‐risk AML. METHODS VPA (5–10 mg/kg starting dose) and ATRA (45 mg/m2) were administered orally. Low‐dose AraC or hydroxyurea were permitted to control leukocytosis. Biologic activity of VPA was confirmed by serial analysis of HDAC2 protein levels in peripheral blood (PB) mononuclear cells. RESULTS Nineteen of 26 patients completed at least 4 weeks of VPA/ATRA treatment; 7 patients were withdrawn prematurely because of rapidly progressive disease (n = 3) or unacceptable neurologic and cardiovascular toxicity (n = 4). Additional cytoreductive treatment was required in 58% of patients enrolled. Median treatment duration was 3 months. No patient achieved complete remission, one with de novo AML had a minor response, and two patients with secondary AML arising from myeloproliferative disorder (MPD) achieved a partial remission and clearance of PB blasts, respectively. The latter responses were accompanied by profound granulocytosis and erythrocytosis in both patients, reminiscent of the response pattern known from ATRA treatment of acute promyelocytic leukemia. However, cytogenetic analysis of isolated CD34+ cells and granulocytes did not reveal terminal differentiation of leukemic blasts. CONCLUSIONS Treatment with VPA/ATRA results in transient disease control in a subset of patients with AML that has evolved from a myeloproliferative disorder but not in patients with a primary or MDS‐related AML. Cancer 2005. © 2005 American Cancer Society.

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Valproic acid induces apoptosis in human leukemia cells by stimulating both caspase-dependent and -independent apoptotic signaling pathways

Cited by 113 publications

References 27 publications

The histone deacetylase inhibitor valproic acid alters sensitivity towards all trans retinoic acid in acute myeloblastic leukemia cells

The histone deacetylase inhibitor valproic acid alters sensitivity towards all trans retinoic acid in acute myeloblastic leukemia cells

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

Clinical trial of valproic acid and all‐trans retinoic acid in patients with poor‐risk acute myeloid leukemia

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