The Design of Selective and Non-selective Combination Therapy for Acute Promyelocytic Leukemia

Jing, Yongkui; Waxman, Samuel

doi:10.1007/978-3-540-34594-7_13

Cited by 10 publications

(9 citation statements)

References 91 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…It is well established that arsenic trioxide induces apoptosis and suppresses the growth of different types of neoplastic cells in vitro and in vivo (1)(2)(3)(4)(5)(6)39). Despite that, the precise up-stream signals that control induction of programmed cell death by As 2 O 3 remain to be elucidated.…”

Section: Discussionmentioning

confidence: 99%

Regulation of Arsenic Trioxide-induced Cellular Responses by Mnk1 and Mnk2

Dolniak

Katsoulidis

Carayol

et al. 2008

Journal of Biological Chemistry

View full text Add to dashboard Cite

The use of arsenic-containing compounds in the treatment of leukemias and other malignancies dates several decades back in time (1). Despite the known existence of arsenic compounds for hundreds of years, only recently has a derivative of this heavy metal, arsenic trioxide (As 2 O 3 ), found an established role in the treatment of a human disease. Extensive work has now established that As 2 O 3 exhibits potent pro-apoptotic effects against malignant cells and has important antineoplastic activities in vitro and in vivo (2-6). Importantly, As 2 O 3 has been approved for the treatment of acute promyelocytic leukemia (APL) 2 in humans, and its introduction in the therapy of this form of acute leukemia has had a major impact in medical oncology (1,(7)(8)(9)(10). Notably, APL is a form of leukemia with unusual sensitivity to the effects of arsenic trioxide. It is well established that induction of differentiation of APL cells occurs at low concentrations (0.5 M), whereas higher (Ն2 M) concentrations are required for the generation of its pro-apoptotic effects in other cell types (2-6). As 2 O 3 is also currently under investigation for the treatment of other hematological malignancies and clonal disorders, including chronic myelogenous leukemia, multiple myeloma, and myelodysplastic syndromes (2, 4, 11-13). A remaining challenge in introducing arsenic trioxide in the treatment of other malignancies is the development of means to enhance arsenic-dependent apoptosis at lower final concentrations. Thus, identification of cellular pathways that could be targeted to enhance the antineoplastic properties of As 2 O 3 are of high translational potential and interest.Previous work has suggested that the pro-apoptotic effects of As 2 O 3 on APL cells correlate with targeting and degradation of the abnormal PML-RAR␣ fusion protein (5, 14, 15), although independent mechanisms also exist (16). Among the genes regulated by the PML-RAR␣ fusion protein is the mitogen-activated protein kinase (MAPK)-interacting kinase 1 (Mnk1) (17, 18), a kinase that was recently shown to be post-translationally stabilized by PML-RAR␣ fusion protein and participate in the control of differentiation of myeloid cells (19). Mnk1 and the related Mnk2 are known to be activated downstream of MAPKs, via phosphorylation at Thr-197 and Thr-202 located in their activation loop (20 -23), and after their activation, they in turn phosphorylate the cap binding eukaryotic initiation factor 4E (eIF4E) at Ser-209 in response to mitogens and stress signals (22,23).In previous work, we had demonstrated that the p38 MAPK is activated in response to treatment of leukemic cells with As 2 O 3 (24) and shown that such activation occurs in a negative feedback regulatory manner, to control and limit arsenic-dependent apoptosis. This was established by studies demonstrating that pharmacological inhibitors of p38 promote generation of As 2 O 3 -dependent apoptosis (24), whereas pro-apoptotic * This work was supported by National Institutes of Health Grants CA121192, CA77816, a...

show abstract

Section: Discussionmentioning

confidence: 99%

Regulation of Arsenic Trioxide-induced Cellular Responses by Mnk1 and Mnk2

Dolniak

Katsoulidis

Carayol

et al. 2008

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…2 In the study reported by Kolb and Steinherz, 2 28 children were treated with TVTG protocol, of which 13 (47%) achieved significant response with acceptable toxicities and 10 (36%) underwent haematopoietic stem cell transplantation. In view of these promising results in the children, we introduced TVTG regimen in adults who have been heavily pretreated for relapsed or refractory leukaemia and high-grade non-hodgkin's lymphoma.…”

Section: Letters To Thementioning

confidence: 99%

“…In the case of one subtype of AML, acute promyelocytic leukemia (APL; FAB M3), differentiation can be induced by all-trans retinoic acid (ATRA), a treatment that is curative for many acute promyelocytic leukemia patients. 1,2 However, ATRA has not proven to be effective in the treatment of other subtypes of AML, underscoring the need to identify new compounds that can either induce differentiation as monotherapies or enhance the efficacy of ATRA therapy. Here we report that the tyrosine kinase inhibitor gefitinib markedly enhances ATRA-induced differentiation in myeloid cell lines.…”

mentioning

confidence: 99%

Gefitinib potentiates myeloid cell differentiation by ATRA

et al. 2008

View full text Add to dashboard Cite

“…Pharmacologic concentrations of ATRA cause a conformational change in the leukemia-generating fusion protein, PML-RARa molecular complex. Corepressors are released, normal retinoic acid receptor-a (RARa)-responsive gene regulation is restored, and terminal APL cell differentiation is induced (5). However, previous studies showed that RARs and their fusion proteins are degraded by the ubiquitin/proteasome pathway (UPP; ref.…”

Section: Introductionmentioning

confidence: 99%

Bortezomib Sensitizes Human Acute Myeloid Leukemia Cells to All-Trans-Retinoic Acid–Induced Differentiation by Modifying the RARα/STAT1 Axis

Ying

Zhou

Zhong

et al. 2013

Molecular Cancer Therapeutics

View full text Add to dashboard Cite

All-trans-retinoic acid (ATRA) has held great promise for differentiation-based therapy but reportedly downregulates retinoic acid receptor-a (RARa) in a proteasome-dependent manner, which leads to decreased acute myeloid leukemia (AML) cell differentiation efficiency. Therefore, research strategies that seek to further sensitize cells to retinoids and extend the range of retinoid-affected myeloid malignancies beyond acute promyelocytic leukemia (APL) are key investigative avenues. Here, we show that bortezomib, the first proteasome inhibitor approved for newly diagnosed and relapsed multiple myeloma, exhibited strong synergism with ATRA to promote HL60 and NB4 AML cell differentiation. We observed that bortezomib sensitized AML cells to ATRA-induced morphologic, biochemical, and functional changes, indicative of myeloid differentiation without cell death. In addition, treatment of human leukemia HL60 xenografts with bortezomib and ATRA together did not increase bortezomib-induced progressive weight loss but resulted in significant tumor growth inhibition in addition to increased differentiation (P < 0.05). These enhanced differentiation effects were accompanied by RARa stabilization and STAT1 activation. Taken together, our study was the first to evaluate bortezomib and ATRA synergy in AML cell differentiation and to assess new opportunities for bortezomib and ATRA combination as a promising approach for future differentiation therapy. Mol Cancer Ther; 12(2); 195-206. Ó2012 AACR.

show abstract

The Design of Selective and Non-selective Combination Therapy for Acute Promyelocytic Leukemia

Cited by 10 publications

References 91 publications

Regulation of Arsenic Trioxide-induced Cellular Responses by Mnk1 and Mnk2

Regulation of Arsenic Trioxide-induced Cellular Responses by Mnk1 and Mnk2

Gefitinib potentiates myeloid cell differentiation by ATRA

Bortezomib Sensitizes Human Acute Myeloid Leukemia Cells to All-Trans-Retinoic Acid–Induced Differentiation by Modifying the RARα/STAT1 Axis

Contact Info

Product

Resources

About