Exploiting Mitochondrial Dysfunction for Effective Elimination of Imatinib-Resistant Leukemic Cells

Kluza, Jérôme; Jendoubi, Manel; Ballot, Caroline; Dammak, Abir; Jonneaux, Aurélie; Idziorek, Thierry; Joha, Sami; Dauphin, Véronique; Malet‐Martino, Myriam; Balayssac, Stéphane; Maboudou, Patrice; Briand, Gilbert; Formstecher, Pierre; Quesnel, Bruno; Marchetti, Philippe

doi:10.1371/journal.pone.0021924

Cited by 51 publications

(57 citation statements)

References 44 publications

(65 reference statements)

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“…These findings confirm that cancer cells possess a highly adaptable metabolism. Reduction in LDH-A activity (40) causes derepression of mitochondrial respiration (25). Inhibition of PDK favors mitochondrial oxidation and ROS production in lung carcinoma (41).…”

Section: Discussionmentioning

confidence: 99%

“…The detection of ROS was determined using the CM-H 2 DCFDA or hydroethidium probe following current protocols (25) and conducted on a FACS Canto II cytofluorometer (Beckton Dickinson). Figure 1.…”

Section: Cytofluorometric Analysismentioning

confidence: 99%

“…The transcript level in each sample was normalized to that of 18S rRNA. The relative expression of target mRNAs was analyzed using the Pfafll method (25).…”

Section: Pcr Analysismentioning

confidence: 99%

“…Metabolites were extracted (26), and profiles were obtained using the 1 H-NMR method as previously described (25).…”

Section: Metabolite Profilesmentioning

confidence: 99%

“…Immunoblotting was conducted as indicated (25). To detect ETC proteins, monoclonal antibodies (OXPHOS complexes kit, MitoSciences; 1:1,000) were used.…”

Section: Immunoblot Analysismentioning

confidence: 99%

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Inactivation of the HIF-1α/PDK3 Signaling Axis Drives Melanoma toward Mitochondrial Oxidative Metabolism and Potentiates the Therapeutic Activity of Pro-Oxidants

et al. 2012

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Cancer cells can undergo a metabolic reprogramming from oxidative phosphorylation to glycolysis that allows them to adapt to nutrient-poor microenvironments, thereby imposing a selection for aggressive variants. However, the mechanisms underlying this reprogramming are not fully understood. Using complementary approaches in validated cell lines and freshly obtained human specimens, we report here that mitochondrial respiration and oxidative phosphorylation are slowed in metastatic melanomas, even under normoxic conditions due to the persistence of a high nuclear expression of hypoxia-inducible factor-1a (HIF-1a). Pharmacologic or genetic blockades of the HIF-1a pathway decreased glycolysis and promoted mitochondrial respiration via specific reduction in the expression of pyruvate dehydrogenase kinase-3 (PDK3). Inhibiting PDK3 activity by dichloroacetate (DCA) or siRNA-mediated attenuation was sufficient to increase pyruvate dehydrogenase activity, oxidative phosphorylation, and mitochondrial reactive oxygen species generation. Notably, DCA potentiated the antitumor effects of elesclomol, a pro-oxidative drug currently in clinical development, both by limiting cell proliferation and promoting cell death. Interestingly, this combination was also effective against BRAF V600E-mutant melanoma cells that were resistant to the BRAF inhibitor vemurafenib. Cotreatment of melanomas with DCA and elesclomol in vivo achieved a more durable response than single agent alone. Our findings offer a preclinical validation of the HIF-1/PDK3 bioenergetic pathway as a new target for therapeutic intervention in metastatic melanoma, opening the door to innovative combinations that might eradicate this disease. Cancer Res; 72(19); 5035-47. Ó2012 AACR.

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Section: Discussionmentioning

confidence: 99%

Section: Cytofluorometric Analysismentioning

confidence: 99%

“…The transcript level in each sample was normalized to that of 18S rRNA. The relative expression of target mRNAs was analyzed using the Pfafll method (25).…”

Section: Pcr Analysismentioning

confidence: 99%

“…Metabolites were extracted (26), and profiles were obtained using the 1 H-NMR method as previously described (25).…”

Section: Metabolite Profilesmentioning

confidence: 99%

“…Immunoblotting was conducted as indicated (25). To detect ETC proteins, monoclonal antibodies (OXPHOS complexes kit, MitoSciences; 1:1,000) were used.…”

Section: Immunoblot Analysismentioning

confidence: 99%

See 3 more Smart Citations

Inactivation of the HIF-1α/PDK3 Signaling Axis Drives Melanoma toward Mitochondrial Oxidative Metabolism and Potentiates the Therapeutic Activity of Pro-Oxidants

et al. 2012

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Relationship of oxidative stress in the resistance to imatinib in Tunisian patients with chronic myeloid leukemia: A retrospective study

Ammar

Mahmoud

Medhaffar

et al. 2019

Clinical Laboratory Analysis

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Background This work aimed to evaluate oxidative stress in chronic myeloid leukemia (CML) patients treated with tunisian (IM) vs controls and in CML patients with resistance to IM vs patients without resistance to IM. Methods The study included 40 CML patients and 34 controls. Of 40 patients with CML, 26 patients were developed in resistance to IM. The oxidant/antioxidant markers were evaluated by spectrophotometric methods for all used samples. Results For CML patients, increased malondialdehyde (MDA) and advanced oxidation protein products (AOPP) levels were found compared to controls (P < .001; P = .01). Higher catalase (CAT) activity (P = .048) and lower superoxide dismutase (SOD) and glutathione peroxidase (GPx) activities, reduced Glutathione (GSH) and vitamin C levels were found in CML patients (P < .001). The comparison between the resistant vs no‐resistant CML patients revealed higher MDA level (P = .02) and CAT and SOD activities in IM‐resistant patients (P = .04, P = .03). GPx activity was reduced (P = .04). Furthermore, increased mean ratio of MDA/GSH, MDA/GPx, and SOD/(GPx + CAT) was found in IM‐resistant patients as compared with no‐resistant (P = .01, P = .01, P = .035). The mean ratio of GPx/GSH in the IM‐resistant CML patients was lower than in IM no‐resistant one (P = .039). For IM‐resistant patients, we found negative correlation between MDA level and the ratio SOD/(CAT + GPx) (r = −0.46, P = .002); and positive correlation between SOD and (CAT + GPx) activities (r = 0.38, P = .06) and between GSH level and GPx activity (r = 0.53, P = .01). Conclusions Our results have shown a highly disturbed oxidative profile in IM‐resistant CML patients as compared to no‐resistant. The H2O2 has a key role in the resistance to IM treatment.

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Canonical and new generation anticancer drugs also target energy metabolism

et al. 2014

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Significant efforts have been made for the development of new anticancer drugs (protein kinase or proteasome inhibitors, monoclonal humanized antibodies) with presumably low or negligible side effects and high specificity. However, an in-depth analysis of the side effects of several currently used canonical (platin-based drugs, taxanes, anthracyclines, etoposides, antimetabolites) and new generation anticancer drugs as the first line of clinical treatment reveals significant perturbation of glycolysis and oxidative phosphorylation. Canonical and new generation drug side effects include decreased (1) intracellular ATP levels, (2) glycolytic/mitochondrial enzyme/transporter activities and/or (3) mitochondrial electrical membrane potentials. Furthermore, the anti-proliferative effects of these drugs are markedly attenuated in tumor rho (0) cells, in which functional mitochondria are absent; in addition, several anticancer drugs directly interact with isolated mitochondria affecting their functions. Therefore, several anticancer drugs also target the energy metabolism, and hence, the documented inhibitory effect of anticancer drugs on cancer growth should also be linked to the blocking of ATP supply pathways. These often overlooked effects of canonical and new generation anticancer drugs emphasize the role of energy metabolism in maintaining cancer cells viable and its targeting as a complementary and successful strategy for cancer treatment.

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Exploiting Mitochondrial Dysfunction for Effective Elimination of Imatinib-Resistant Leukemic Cells

Cited by 51 publications

References 44 publications

Inactivation of the HIF-1α/PDK3 Signaling Axis Drives Melanoma toward Mitochondrial Oxidative Metabolism and Potentiates the Therapeutic Activity of Pro-Oxidants

Inactivation of the HIF-1α/PDK3 Signaling Axis Drives Melanoma toward Mitochondrial Oxidative Metabolism and Potentiates the Therapeutic Activity of Pro-Oxidants

Relationship of oxidative stress in the resistance to imatinib in Tunisian patients with chronic myeloid leukemia: A retrospective study

Canonical and new generation anticancer drugs also target energy metabolism

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