Complex I inhibition augments dichloroacetate cytotoxicity through enhancing oxidative stress in VM-M3 glioblastoma cells

Ward, Nathan P.; Poff, Angela M.; Koutnik, Andrew P.; D’Agostino, Dominic P.

doi:10.1371/journal.pone.0180061

Cited by 25 publications

(25 citation statements)

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“…A mechanism by which DCA may affect cell viability is through inhibition of PDK and increased ROS production. In this regard, DCA was previously shown to inhibit PDK in different tumor cell lines, resulting in dephosphorylation and reactivation of the PDH complex 33 , that promotes oxidative phosphorylation leading to increased ROS production 35 – 37 . To evaluate whether DCA treatment induced dephosphorylation of PDH in PGL cells, we analyzed by western blotting the phosphorylation status of the PDH-E1α subunit.…”

Section: Resultsmentioning

confidence: 99%

Effects of dichloroacetate as single agent or in combination with GW6471 and metformin in paraganglioma cells

Florio

Lellis

Veschi

et al. 2018

Sci Rep

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Paragangliomas (PGLs) are infiltrating autonomic nervous system tumors that cause important morbidity. At present, surgery is the only effective therapeutic option for this rare tumor. Thus, new agents for PGL treatment should be identified. Using unique PGL cell models established in our laboratory, we evaluated the effect of dichloroacetate (DCA) as single agent or in a novel combination with other metabolic drugs, including GW6471 and metformin. DCA and metformin had not been tested before in PGL. DCA reduced PGL cell viability and growth through mechanisms involving reactivation of PDH complex leading to promotion of oxidative metabolism, with lowering of lactate and enhanced ROS production. This resulted in cell cycle inhibition and induction of apoptosis in PGL cells, as shown by flow cytometry and immunoblot analyses. Moreover, DCA drastically impaired clonogenic activity and migration of PGL cells. Also metformin reduced PGL cell viability as single agent and the combinations of DCA, GW6471 and metformin had strong effects on cell viability. Furthermore, combined treatments had drastic and synergistic effects on clonogenic ability. In conclusion, DCA, GW6471 and metformin as single agents and in combination appear to have promising antitumor effects in unique cell models of PGL.

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Section: Resultsmentioning

confidence: 99%

Effects of dichloroacetate as single agent or in combination with GW6471 and metformin in paraganglioma cells

Florio

Lellis

Veschi

et al. 2018

Sci Rep

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“…As Ward et al proposed, the detected synergism between DCA and metformin can be best exploited with another pro-oxidant compound (12). As our study suggests, this compound could be PX-478, which would lead to an interesting triple combination.…”

Section: And 5)mentioning

confidence: 51%

“…DCA was found to normalize this axis and thereby induce the apoptosis of cancer cells (8,9). In addition to its effects on the mitochondrial membrane potential, DCA is believed to lead to a signi cant increase in reactive oxygen species (ROS) generation, which plays an important role in the induction of apoptosis (10)(11)(12)(13)(14). By contrast, other authors reported that DCA may function as a sensitizer for ROS induced alterations, but did not signi cantly increase ROS production per se (13,15).…”

Section: Compoundsmentioning

confidence: 99%

“…As DCA has attracted considerable attention in recent years, many examples of synergism have been detected. 5uorouracil, platinum-based chemotherapy, a SIRT2 inhibitor, Metformin, omeprazole + tamoxifen, sorafenib, erlotinib and ge tinib, have been shown to have synergistic effects in combination with DCA in vivo and in vitro (12,54,65,(57)(58)(59)(60)(61)(62)(63)(64).…”

Section: And 5)mentioning

confidence: 99%

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Dichloroacetate and PX-478 Exhibit Strong Synergistic Effects in a Various Number of Cancer Cell Lines.

Parczyk

Ruhnau

Pelz

et al. 2020

Preprint

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Background: One key approach for anticancer therapy is drug combination. Drug combinations can help reduce doses and thereby decrease side effects. Further, the likelihood of drug resistance is reduced. Distinct alterations in tumour metabolism have been described in past decades, but metabolism has yet to be targeted in clinical cancer therapy. Recently, we found evidence for a synergism between dichloroacetate (DCA), a pyruvate dehydrogenase kinase inhibitor and HIF1-α inhibitor PX-478. In this study, we aimed to analyse this synergism in cell lines of different cancer types and to identify the underlying biochemical mechanisms.Methods: The dose-dependent antiproliferative effects of the single drugs and their combination were assessed using MTT or SRB assays. FACS, Western blot and HPLC analyses were performed to investigate changes in reactive oxygen species levels, apoptosis and the cell cycle. Additionally, real-time metabolic analyses (Seahorse) were performed with DCA-treated MCF-7 cells.Results: The combination of DCA and PX-478 produced synergistic effects in all eight cancer cell lines tested, including colorectal, lung, breast, cervical, liver and brain cancer. Reactive oxygen species generation and apoptosis played important roles in this synergism. Furthermore, cell proliferation was inhibited by the combination treatment.Conclusions: Here, we found that these cancer metabolism-targeting compounds exhibited potent synergism across all tested cancer cell lines. Thus, we highly recommend the combination of these two compounds for progression to in vivo translational and clinical trials.

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“…Furthermore, it impaired DNA and other components of the mitochondrial via the increasing of ROS level (Higgins & Greenamyre, ). Thus, it stimulated apoptosis in different cells, for instance, glioblastoma (Ward, Poff, Koutnik, & D'Agostino, ), leukemia (Diaz‐Aguirre, Velez‐Pardo, & Jimenez‐Del‐Rio, ), cervical (Agarwal, Maurya, Pawar, & Ghosh, ), lung (Hu et al, ), neuroblastoma (Kabiraj et al, ), and liver (Badaboina et al, ) cancerous cells. Other flavonoid, medcarpin, which isolated from medicago sativa, induced apoptosis and defeated multidrug resistance in breast (Le Bail, Champavier, Chulia, & Habrioux, ) and leukemia P388 cells (Gatouillat et al, ).…”

Section: Intracellular Anti‐apoptotic Proteins As Targeted Therapymentioning

confidence: 99%

Down‐regulation of intracellular anti‐apoptotic proteins, particularly c‐FLIP by therapeutic agents; the novel view to overcome resistance to TRAIL

Hassanzadeh

Hagh

Alivand

et al. 2018

Journal Cellular Physiology

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Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL or Apo2L) is a member of the tumor necrosis factor (TNF) superfamily that induces apoptosis in different types of cancer cells via activation of caspase cascade. TRAIL interacts with its cognate receptors that placed on cancer cells surface, including TRAIL-R1 (death receptor 4, DR4), TRAIL-R2 (death receptor 5, DR5), TRAIL-R3 (decoy receptor 1, DcR1), TRAIL-R4 (decoy receptor 2, DcR2), and osteoprotegerin (OPG). Despite high apoptosis-inducing ability of TRAIL, various cancerous cells gain resistance to TRAIL gradually, and consequently TRAIL potential for apoptosis stimulation in these cells diminishes intensely. According to diverse ranges of examinations, intracellular anti-apoptotic proteins, such as cellular-FLICE inhibitory protein (c-FLIP), apoptosis inhibitors (IAPs), myeloid cell leukemia sequence 1 (MCL-1), BCL-2, BCL-XL, and survivin play key role in cancer cells resistance to TRAIL. These proteins attenuate cancer cells sensitivity to TRAIL via various functions, importantly through caspase cascade suppression. The c-FLIP avoids from caspase 8 activation by FADD via binding to caspase 8 cleavage of FADD. Moreover, it activates signaling pathways that involved in cancer cells survival and proliferation. Intriguingly, it appears that the down-regulation of intracellular anti-apoptotic proteins, particularly c-FLIP is effectiveness goal for TRAIL-resistant cancers therapy, because their up-regulation in association with poor prognosis has been observed in various types of TRAIL-resistant cancers. In this review, we tried to collect and examine investigations that researchers have been able to sensitize cancer cells to TRAIL through targeting of c-FLIP alone or with other intracellular anti-apoptotic proteins directly or indirectly. It seems that co-treatment of resistant cells by TRAIL with other therapeutic agents with the aim of intracellular anti-apoptotic proteins inhibition is hopeful and attractive approach to overcome various TRAIL-resistant cancers.

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Complex I inhibition augments dichloroacetate cytotoxicity through enhancing oxidative stress in VM-M3 glioblastoma cells

Cited by 25 publications

References 71 publications

Effects of dichloroacetate as single agent or in combination with GW6471 and metformin in paraganglioma cells

Effects of dichloroacetate as single agent or in combination with GW6471 and metformin in paraganglioma cells

Dichloroacetate and PX-478 Exhibit Strong Synergistic Effects in a Various Number of Cancer Cell Lines.

Down‐regulation of intracellular anti‐apoptotic proteins, particularly c‐FLIP by therapeutic agents; the novel view to overcome resistance to TRAIL

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