A small molecule interacts with VDAC2 to block mouse BAK-driven apoptosis

Delft, Mark F. van; Chappaz, Stéphane; Khakham, Yelena; Bui, Chinh T.; Debrincat, Marlyse A.; Lowes, Kym N.; Brouwer, J.M.; Grohmann, Christoph; Sharp, Phillip P.; Dagley, Laura F.; Li, Lucy; Luo, Meng; Chin, Hui San; Fairlie, W. Douglas; Lee, Erinna F.; Segal, David; Duflocq, Stephane; Lessene, Romina; Bernard, Suzanne; Peilleron, Laure; Nguyen, Thao; Miles, Caroline S.; Wan, Soo San; Lane, Rachael M.; Wardak, Ahmad; Lackovic, Kurt; Colman, Peter M.; Sandow, Jarrod J.; Webb, Andrew I.; Czabotar, P.E.; Dewson, Grant; Watson, Keith G.; Huang, David C.S.; Lessène, Guillaume; Kile, Benjamin T.

doi:10.1038/s41589-019-0365-8

Cited by 38 publications

(54 citation statements)

References 58 publications

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“…Direct activators of BAK may best recruit additional pore-forming BAK and BAX molecules to induce robust apoptosis in cancer cells. Direct inhibitors of BAK, including small molecules 65 , by precluding autoactivation, may be particularly effective in inhibiting unwanted apoptosis.…”

Section: Discussionmentioning

confidence: 99%

Robust autoactivation for apoptosis by BAK but not BAX highlights BAK as an important therapeutic target

et al. 2020

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BAK and BAX, which drive commitment to apoptosis, are activated principally by certain BH3-only proteins that bind them and trigger major rearrangements. One crucial conformation change is exposure of their BH3 domain which allows BAK or BAX to form homodimers, and potentially to autoactivate other BAK and BAX molecules to ensure robust pore formation and cell death. Here, we test whether full-length BAK or mitochondrial BAX that are specifically activated by antibodies can then activate other BAK or BAX molecules. We found that antibody-activated BAK efficiently activated BAK as well as mitochondrial or cytosolic BAX, but antibody-activated BAX unexpectedly proved a poor activator. Notably, autoactivation by BAK involved transient interactions, as BAK and BAX molecules it activated could dissociate and homodimerize. The results suggest that BAK-driven autoactivation may play a substantial role in apoptosis, including recruitment of BAX to the mitochondria. Hence, directly targeting BAK rather than BAX may prove particularly effective in inhibiting unwanted apoptosis, or alternatively, inducing apoptosis in cancer cells.

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Section: Discussionmentioning

confidence: 99%

Robust autoactivation for apoptosis by BAK but not BAX highlights BAK as an important therapeutic target

et al. 2020

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“…However, while many drugs affecting VDAC1 have been identified, those specifically acting on the other isoforms are less investigated. A recent work identified WEHI-9625, a novel tricyclic sulfone small molecule, that was able to bind to VDAC2 and inhibit Bak-triggered apoptosis [ 116 ], suggesting that an activator rather than an inhibitor of VDAC2 would be useful to eliminate cancer cells.…”

Section: Mitochondrial Ion Channels and Their Pharmacological Targeting By Small Moleculesmentioning

confidence: 99%

Targeting mitochondrial ion channels for cancer therapy

2021

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Pharmacological targeting of mitochondrial ion channels is emerging as a promising approach to eliminate cancer cells; as most of these channels are differentially expressed and/or regulated in cancer cells in comparison to healthy ones, this strategy may selectively eliminate the former. Perturbation of ion fluxes across the outer and inner membranes is linked to alterations of redox state, membrane potential and bioenergetic efficiency. This leads to indirect modulation of oxidative phosphorylation, which is/may be fundamental for both cancer and cancer stem cell survival. Furthermore, given the crucial contribution of mitochondria to intrinsic apoptosis, modulation of their ion channels leading to cytochrome c release may be of great advantage in case of resistance to drugs triggering apoptotic events upstream of the mitochondrial phase. In the present review, we give an overview of the known mitochondrial ion channels and of their modulators capable of killing cancer cells. In addition, we discuss state-of-the-art strategies using mitochondriotropic drugs or peptide-based approaches allowing a more efficient and selective targeting of mitochondrial ion channel-linked events.

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“…Activating apoptosis pathway with chemical drugs was a clinically validated approach to cancer therapy. 21 Our data by flow cytometry showed that the late stage apoptotic rate increased in MDA-MB-231 cells treated with AS-605240 and/or PTX ( Figure 3A). The late apoptotic rate was the highest when using the combined treatment ( Figure 3B).…”

Section: The Apoptotic Rate Of Clbc Cells Induced By Ptx Was Enforcedmentioning

confidence: 76%

<p>Targeting PIK3CG in Combination with Paclitaxel as a Potential Therapeutic Regimen in Claudin-Low Breast Cancer</p>

Chang¹,

Ling²,

Liu³

et al. 2020

CMAR

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Purpose: Molecular targeting is a powerful approach for aggressive claudin-low breast cancer (CLBC). Overexpression of PI3K catalytic subunit gamma (PIK3CG) in human CLBC is offering a promising opportunity for targeted therapies. We utilized a specific inhibitor of PIK3CG combined with paclitaxel (PTX) to treat CLBC cells in vitro and in vivo. Patients and Methods: The tumor cells growth and apoptosis in vitro were analyzed by CCK8, plate clone formation assay, tumorsphere assay, Hoechst staining and flow cytometry. The invasion and metastasis ability of tumor cells in vitro were investigated by wound healing and transwell experiments. Critical gene expression levels were checked by qRT-PCR and Western blot. Xenograft models with CLBC cell lines in SCID mice were established to investigate the effect of combined drugs in vivo. Results: We identified that PIK3CG was a potential therapeutic target for CLBC patients. Targeting PIK3CG potentiated CLBC cells growth inhibition in 2D and 3D cultures by PTX. Inhibition of PIK3CG activation could enhance CLBC cells apoptosis and migration suppression induced by PTX. Manipulating autophagy was a validated approach for the use of PIK3CG inhibitor. Using CLBC xenograft mice model, we found that CLBC tumors in vivo could be well treated by combined drugs of PIK3CG inhibitor and PTX. Conclusion: We demonstrated that PIK3CG was a potential target for the therapy of CLBC and inhibition of PIK3CG activation could reinforce the therapeutic effect of this aggressive disease by PTX. The combined use of PIK3CG inhibitor and PTX might be a potential regimen for treating this subtype of breast cancer.

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A small molecule interacts with VDAC2 to block mouse BAK-driven apoptosis

Cited by 38 publications

References 58 publications

Robust autoactivation for apoptosis by BAK but not BAX highlights BAK as an important therapeutic target

Robust autoactivation for apoptosis by BAK but not BAX highlights BAK as an important therapeutic target

Targeting mitochondrial ion channels for cancer therapy

<p>Targeting PIK3CG in Combination with Paclitaxel as a Potential Therapeutic Regimen in Claudin-Low Breast Cancer</p>

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