Development of Noxa-like BH3 Mimetics for Apoptosis-Based Therapeutic Strategy in Chronic Lymphocytic Leukemia

Billard, Christian

doi:10.1158/1541-7786.mcr-12-0015

Cited by 11 publications

(6 citation statements)

References 32 publications

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“…Noxa, a BH3-only protein, specifically binds to Mcl-1 and then leads to Bak activation and apoptosis [9]. Based on the specificity of Noxa binding to Mcl-1, Noxa mimetics are being developed [43]. Several agents approved for cancer therapy such as bortezomib have been found to induce Noxa expression [44].…”

Section: Discussionmentioning

confidence: 99%

Dihydroartemisinin and its derivative induce apoptosis in acute myeloid leukemia through Noxa-mediated pathway requiring iron and endoperoxide moiety

et al. 2015

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Anti-apoptotic protein Mcl-1 plays an important role in protecting cell from death in acute myeloid leukemia (AML). The apoptosis blocking activity of Mcl-1 is inhibited by BH3-only protein Noxa. We found that dihydroartemisinin (DHA) and its derivative X-11 are potent apoptosis inducers in AML cells and act through a Noxa-mediate pathway; X-11 is four-fold more active than DHA. DHA and X-11-induced apoptosis is associated with induction of Noxa; apoptosis is blocked by silencing Noxa. DHA and X-11 induce Noxa expression by upregulating the transcription factor FOXO3a in a reactive oxygen species-mediated pathway. Interfering with the integrity of the endoperoxide moiety of DHA and X-11, as well as chelating intracellular iron with deferoxamine, diminish apoptosis and Noxa induction. AML cells expressing Bcl-xL, or with overexpression of Bcl-2, have decreased sensitivity to DHA and X-11-induced apoptosis which could be overcome by addition of Bcl-2/Bcl-xL inhibitor ABT-737. DHA and X-11 represent a new group of AML cells-apoptosis inducing compounds which work through Noxa up-regulation utilizing the specific endoperoxide moiety and intracellular iron.

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Section: Discussionmentioning

confidence: 99%

Dihydroartemisinin and its derivative induce apoptosis in acute myeloid leukemia through Noxa-mediated pathway requiring iron and endoperoxide moiety

et al. 2015

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“…Lastly, it must be borne in mind that Noxa can be upregulated by the inhibition of proteasomal activities and that some flavonoids capable of inducing apoptosis in CLL cells have also been characterized as natural proteasome inhibitors (EGCG, quercetin, apigenin). Given that Noxa can bind to Mcl-1 but not other survival Bcl-2 proteins and that Mcl-1 clearly has a critical antiapoptotic role, the Noxa/Mcl-1 axis is an attractive target for apoptosis-based strategies in CLL [116,117]. …”

Section: Comments and Discussionmentioning

confidence: 99%

Apoptosis inducers in chronic lymphocytic leukemia

Billard

2013

Oncotarget

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Chronic lymphocytic leukemia (CLL) is characterized by a typical defect in apoptosis and is still an incurable disease. Numerous apoptosis inducers have been described. These synthetic compounds and natural products (mainly derived from plants) display antileukemic properties in vitro and in vivo and some have even been tested in the clinic in CLL. They act through several different mechanisms. Most of them involve proteins of the Bcl-2 family, which are the key regulators in triggering the mitochondrial pathway of caspase-dependent apoptosis. Thus, the Mcl-1/Noxa axis appeared as a target. Here I overview natural and synthetic apoptosis inducers and their mechanisms of action in CLL cells. Opportunities for developing novel, apoptosis-based therapeutics are presented.

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“…This highlights the need to develop drugs that directly target MCL-1. However, none of the current agents binds MCL-1 with high affinity [80]. A few compounds in preclinical studies designed from the BH3 domain of BIM or MCL-1 show MCL-1–dependent proapoptotic activity and have the potential to be developed as MCL-1 inhibitors [81,82].…”

Section: Targeting the Apoptosis Pathwaymentioning

confidence: 99%

Targeting the apoptosis pathway in hematologic malignancies

Zaman¹,

Wang²,

Gandhi³

2014

Leukemia & Lymphoma

186

146

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Apoptosis is a cell death program that is well-orchestrated for normal tissue homeostasis and for removal of damaged, old, or infected cells. It is regulated by intrinsic and extrinsic pathways. The intrinsic pathway responds to signals such as ultraviolet radiation or DNA damage and activates “executioner” caspases through a mitochondria-dependent pathway. The extrinsic pathway is activated by death signals induced, for example, by an infection that activates the immune system or receptor-mediated pathways. The extrinsic pathway signals also cascade down to executioner caspases that cleave target proteins and lead to cell death. Strict control of cellular apoptosis is important for the hematopoietic system as it has a high turnover rate. However, the apoptosis program is often deregulated in hematologic malignancies leading to the accumulation of malignant cells. Therefore, apoptosis pathways have been identified for development of anticancer therapeutics. We review here the proteins that have been targeted for anticancer drug development in hematologic malignancies. These include BCL-2 family proteins, death ligands and receptors, inhibitor of apoptosis family proteins, and caspases. Except for caspase activators, drugs that target each of these classes of proteins have advanced into clinical trials.

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Development of Noxa-like BH3 Mimetics for Apoptosis-Based Therapeutic Strategy in Chronic Lymphocytic Leukemia

Abstract: Despite real advances made in chemoimmunotherapy, chronic lymphocytic leukemia (CLL) is still an incurable disease. New therapeutic strategies based on the restoration of the cell death program seemed relevant.

Cited by 11 publications

References 32 publications

Dihydroartemisinin and its derivative induce apoptosis in acute myeloid leukemia through Noxa-mediated pathway requiring iron and endoperoxide moiety

Dihydroartemisinin and its derivative induce apoptosis in acute myeloid leukemia through Noxa-mediated pathway requiring iron and endoperoxide moiety

Apoptosis inducers in chronic lymphocytic leukemia

Targeting the apoptosis pathway in hematologic malignancies

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