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Cited by 184Cancer, Hypoxia, and MetabolismMetabolism, Diabetes, and CancerPancreatic and Hepatic Oncology Research

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Targeting Mitochondrial Complex I Overcomes Chemoresistance in High OXPHOS Pancreatic Cancer

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Masoud, Rawand, Reyes-Castellanos, Gabriela, Lac, Sophie, Garcia, Julie, Dou, Samir, Shintu, Laetitia, Abdel Hadi, Nadine, Gicquel, Tristan, El Kaoutari, Abdessamad, Diémé, Binta, Tranchida, Fabrice, Cormareche, Laurie, Borge, Laurence, Gayet, Odile, Pasquier, Eddy, Dusetti, Nelson, Iovanna, Juan, Carrier, Alice·2020·Cell Reports Medicine
DOI 10.1016/j.xcrm.2020.100143PMC PMC7691450
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Abstract

Mitochondrial respiration (oxidative phosphorylation, OXPHOS) is an emerging target in currently refractory cancers such as pancreatic ductal adenocarcinoma (PDAC). However, the variability of energetic metabolic adaptations between PDAC patients has not been assessed in functional investigations. In this work, we demonstrate that OXPHOS rates are highly heterogeneous between patient tumors, and that high OXPHOS tumors are enriched in mitochondrial respiratory complex I at protein and mRNA levels. Therefore, we treated PDAC cells with phenformin (complex I inhibitor) in combination with standard chemotherapy (gemcitabine), showing that this treatment is synergistic specifically in high OXPHOS cells. Furthermore, phenformin cooperates with gemcitabine in high OXPHOS tumors in two orthotopic mouse models (xenografts and syngeneic allografts). In conclusion, this work proposes a strategy to identify PDAC patients likely to respond to the targeting of mitochondrial energetic metabolism in combination with chemotherapy, and that phenformin should be clinically tested in appropriate PDAC patient subpopulations.

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Graphical abstract CC BY-NC-ND · PubMed Central
Figure 1 Stratification of PDAC Tumors According to Their Energetic Metabolism (A) Oxygen consumption rate (OCR) was measured in the 6 classical PDAC cell lines under basal conditions and following the injection of oligomycin, carbonyl cyanide-p-trifluoromethoxyphenyl-hydrazon (FCCP), and rotenone + antimycin A. (B) Extracellular acidification rate (ECAR) was measured under basal conditions and following the addition of glucose, oligomycin, and 2-deoxyglucose. (C) Basal OCR versus basal ECAR plot (both normalized to 10,000 seeded cells) shows the clustering of the 6 PDAC classical cell lines into 3 metabolic groups: Panc-1 is mostly respiratory (OXPHOS); MIA PaCa-2 and BxPC-3 are mostly glycolytic (glycolytic); and Capan-1, Capan-2, and to a lesser extent SOJ-6, have a relative lower energetic metabolism compared to the other cell lines (less metabolic group). The dotted lines indicate the thresholds that we selected between high and low OCR and ECAR. (D) Basal OCR versus basal ECAR plot (both normalized to 10,000 seeded cells) shows the clustering of the 21 primary PDAC cancer cells derived from PDX into 4 different groups with respect to their basal energetic features. A fourth group with high rates of both OCR and ECAR was found. High OXPHOS patients are depicted with the red color, and low OXPHOS with blue color. The dotted lines indicate the thresholds that we selected between high and low OCR and ECAR. This plot is representative of at least 3 independent experiments for each patient. For clarity, a short version of the anonymized name of patients is used. Representative profiles of at least 3 independent experiments are shown in (A) and (B). See also Figures S1 and S2 and Table S1.
Figure 1 Stratification of PDAC Tumors According to Their Energetic Metabolism (A) Oxygen consumption rate (OCR) was measured in the 6 classical PDAC cell lines under basal conditions and following the injection of oligomycin, carbonyl cyanide-p-trifluoromethoxyphenyl-hydrazon (FCCP), and rotenone + antimycin A. (B) Extracellular acidification rate (ECAR) was measured under basal conditions and following the addition of glucose, oligomycin, and 2-deoxyglucose. (C) Basal OCR versus basal ECAR plot (both normalized to 10,000 seeded cells) shows the clustering of the 6 PDAC classical cell lines into 3 metabolic groups: Panc-1 is mostly respiratory (OXPHOS); MIA PaCa-2 and BxPC-3 are mostly glycolytic (glycolytic); and Capan-1, Capan-2, and to a lesser extent SOJ-6, have a relative lower energetic metabolism compared to the other cell lines (less metabolic group). The dotted lines indicate the thresholds that we selected between high and low OCR and ECAR. (D) Basal OCR versus basal ECAR plot (both normalized to 10,000 seeded cells) shows the clustering of the 21 primary PDAC cancer cells derived from PDX into 4 different groups with respect to their basal energetic features. A fourth group with high rates of both OCR and ECAR was found. High OXPHOS patients are depicted with the red color, and low OXPHOS with blue color. The dotted lines indicate the thresholds that we selected between high and low OCR and ECAR. This plot is representative of at least 3 independent experiments for each patient. For clarity, a short version of the anonymized name of patients is used. Representative profiles of at least 3 independent experiments are shown in (A) and (B). See also Figures S1 and S2 and Table S1.CC BY-NC-ND · PubMed Central
Figure 2 Structure of Mitochondria and Abundance of Respiratory Complex I Reflect Respiration Activity (A and B) Flow cytometry analysis of the classical PDAC cells was carried out using (A) MitoTracker DeepRed for mitochondrial mass, and (B) MITO-ID for analysis of the mitochondrial membrane potential. Data are presented as the mean of triplicates ± SEMs. Statistically significant differences between Panc-1 cell line with the 5 other cell lines: ∗p < 0.05, ns = not significant. Data are representative of 3 independent experiments. (C) The ratio of mitochondrial membrane potential:mitochondrial mass was calculated from (A) and (B). (D and E) Representative transmission electron microscopy images are shown at different magnifications. The scale is indicated in the lower right part of each image. High magnification is shown in the inset in (E). (F) Top: Representative immunoblot showing the abundance of 5 mitochondrial proteins (ATP5A, UQCR2, SDHB, COXII, and NDUFB8) belonging to respiratory chain complexes (V, III, II, IV, and I, respectively). Time exposure of the blot was 5 s for ATP5A while the rest was 1 min 30 s. Ponceau red staining was used as the control of equal protein loading (not shown). Bottom: Representative immunoblot showing the abundance of the protein NDUFB8 belonging to mitochondrial complex I. The time exposure was 1 min. Ponceau red staining was used as the control of equal protein loading (not shown). In both blots, an irrelevant lane was spliced out (vertical black line). (G) Heatmap of differential metabolites between the 6 cell lines. Twelve metabolites were selected according to the results from the OPLS-DA differentiating OXPHOS Panc-1 cells from glycolytic MIA PaCa-2 and BxPC-3 cells (N = 21; 1 predictive + 1 orthogonal OPLS-DA model with R2Y = 0.93; QY = 0.87 ; CV_ANOVA p value = 2.10–6). Data have been Pareto scaled. Each column is the autoscaled mean abundance (isolated NMR signal integration) of each metabolite ranging from dark blue (−1) to dark red (1). Unsat fatty acids, unsaturated fatty acids; GPC, glycerophosphocholine; PC, phosphocholine. Proline is the dominant metabolite in Panc-1, SOJ-6, BxPC-3, and MIA PaCa-2; taurine is the dominant metabolite in Capan-1 and Capan-2. See also Figures S3 and S4.
Figure 2 Structure of Mitochondria and Abundance of Respiratory Complex I Reflect Respiration Activity (A and B) Flow cytometry analysis of the classical PDAC cells was carried out using (A) MitoTracker DeepRed for mitochondrial mass, and (B) MITO-ID for analysis of the mitochondrial membrane potential. Data are presented as the mean of triplicates ± SEMs. Statistically significant differences between Panc-1 cell line with the 5 other cell lines: ∗p < 0.05, ns = not significant. Data are representative of 3 independent experiments. (C) The ratio of mitochondrial membrane potential:mitochondrial mass was calculated from (A) and (B). (D and E) Representative transmission electron microscopy images are shown at different magnifications. The scale is indicated in the lower right part of each image. High magnification is shown in the inset in (E). (F) Top: Representative immunoblot showing the abundance of 5 mitochondrial proteins (ATP5A, UQCR2, SDHB, COXII, and NDUFB8) belonging to respiratory chain complexes (V, III, II, IV, and I, respectively). Time exposure of the blot was 5 s for ATP5A while the rest was 1 min 30 s. Ponceau red staining was used as the control of equal protein loading (not shown). Bottom: Representative immunoblot showing the abundance of the protein NDUFB8 belonging to mitochondrial complex I. The time exposure was 1 min. Ponceau red staining was used as the control of equal protein loading (not shown). In both blots, an irrelevant lane was spliced out (vertical black line). (G) Heatmap of differential metabolites between the 6 cell lines. Twelve metabolites were selected according to the results from the OPLS-DA differentiating OXPHOS Panc-1 cells from glycolytic MIA PaCa-2 and BxPC-3 cells (N = 21; 1 predictive + 1 orthogonal OPLS-DA model with R2Y = 0.93; QY = 0.87 ; CV_ANOVA p value = 2.10–6). Data have been Pareto scaled. Each column is the autoscaled mean abundance (isolated NMR signal integration) of each metabolite ranging from dark blue (−1) to dark red (1). Unsat fatty acids, unsaturated fatty acids; GPC, glycerophosphocholine; PC, phosphocholine. Proline is the dominant metabolite in Panc-1, SOJ-6, BxPC-3, and MIA PaCa-2; taurine is the dominant metabolite in Capan-1 and Capan-2. See also Figures S3 and S4.CC BY-NC-ND · PubMed Central
Figure 3 Correlation between the High OXPHOS Status and the Abundance of Mitochondrial Complex I, Both at mRNA and Protein Level in the Primary PDAC Cancer Cells High OXPHOS patients are depicted in red, and low OXPHOS are in blue. (A) Canonical correlation analysis: graphical representation of PDX using the averaged components 1 and 2 of transcriptomic and metabolic datasets that were retrieved from canonical PLS. (B) Gene set enrichment analysis: the two plots show the enrichment score for the related mitochondrial pathway on the second canonical PLS component in (A). (C) Representative immunoblot showing the abundance of the 5 mitochondrial proteins (ATP5A, UQCR2, SDHB, COXII, and NDUFB8) belonging to mitochondrial complexes (V, III, II, IV, and I, respectively). Time exposure of the blot was 1 min. Ponceau red staining was used as the control of equal protein loading. Mitochondrial complexes protein levels were quantified from western blotting (WB) by ImageJ and normalized to Ponceau red staining. p value from Mann-Whitney test. (D) Representative immunoblot showing the abundance of the mitochondrial protein NDUFB8 belonging to mitochondrial complex I. Time exposure of the blot was 1 min. Complex I protein was quantified by ImageJ and normalized to Ponceau red staining used as control of equal protein loading. p value from Mann-Whitney test. (E) Metabolic analysis by HRMAS-NMR for 6 primary PDAC cancer cells derived from PDX, 3 high OXPHOS (27, 74, and 84) and 3 low OXPHOS (22, 32, and 85). OPLSDA score plot showing the discrimination between high OXPHOS and low OXPHOS. (F) Kaplan-Meier survival curve using transcriptomic analysis on patient-derived xenografts, divided into high and low NDUFB8 gene expression groups (n = 40 and n = 35, respectively; the cutpoint was 13.22). p value was calculated by the log-rank test. See also Figures S5 and S6 and Table S2.
Figure 3 Correlation between the High OXPHOS Status and the Abundance of Mitochondrial Complex I, Both at mRNA and Protein Level in the Primary PDAC Cancer Cells High OXPHOS patients are depicted in red, and low OXPHOS are in blue. (A) Canonical correlation analysis: graphical representation of PDX using the averaged components 1 and 2 of transcriptomic and metabolic datasets that were retrieved from canonical PLS. (B) Gene set enrichment analysis: the two plots show the enrichment score for the related mitochondrial pathway on the second canonical PLS component in (A). (C) Representative immunoblot showing the abundance of the 5 mitochondrial proteins (ATP5A, UQCR2, SDHB, COXII, and NDUFB8) belonging to mitochondrial complexes (V, III, II, IV, and I, respectively). Time exposure of the blot was 1 min. Ponceau red staining was used as the control of equal protein loading. Mitochondrial complexes protein levels were quantified from western blotting (WB) by ImageJ and normalized to Ponceau red staining. p value from Mann-Whitney test. (D) Representative immunoblot showing the abundance of the mitochondrial protein NDUFB8 belonging to mitochondrial complex I. Time exposure of the blot was 1 min. Complex I protein was quantified by ImageJ and normalized to Ponceau red staining used as control of equal protein loading. p value from Mann-Whitney test. (E) Metabolic analysis by HRMAS-NMR for 6 primary PDAC cancer cells derived from PDX, 3 high OXPHOS (27, 74, and 84) and 3 low OXPHOS (22, 32, and 85). OPLSDA score plot showing the discrimination between high OXPHOS and low OXPHOS. (F) Kaplan-Meier survival curve using transcriptomic analysis on patient-derived xenografts, divided into high and low NDUFB8 gene expression groups (n = 40 and n = 35, respectively; the cutpoint was 13.22). p value was calculated by the log-rank test. See also Figures S5 and S6 and Table S2.CC BY-NC-ND · PubMed Central
Figure 4 Targeting Mitochondrial Respiratory Complex I with Phenformin Synergizes with Gemcitabine Antitumoral Activity in High OXPHOS Cells (A and B) Dose-response curves for the 6 classical PDAC cell lines treated with different concentrations of gemcitabine (A) or phenformin (B) for 72 h. Live cells are indicated as a percentage of the control (vehicle treated). Data are means of triplicates ± SEMs. Data are representative of 3 independent experiments. The 0.5 mM concentration of phenformin is highlighted by a vertical dotted line in (B). The IC50 of phenformin was calculated and is shown on the right of the dose-response curve. (C) Representative dose-response curves for the 6 PDAC cell lines treated with low concentrations of gemcitabine alone (blue curves) and gemcitabine in combination with 0.5 mM phenformin (red curves) for 72 h. Cell viability is indicated as a percentage of the control (vehicle treated). Data are means of triplicates ± SEMs. (D) Representative dose-response curves for 6 primary PDAC cancer cells derived from PDX, 3 high OXPHOS (27, 74, and 84) and 3 low OXPHOS (22, 32, and 85). Cells were treated for 72 h with low concentrations of gemcitabine alone (blue curves) and in combination with 0.5 mM phenformin (red curves). Cell viability is indicated as the percentage of the control (vehicle treated). Data are means of triplicates ± SEMs. See also Figures S7 and S8.
Figure 4 Targeting Mitochondrial Respiratory Complex I with Phenformin Synergizes with Gemcitabine Antitumoral Activity in High OXPHOS Cells (A and B) Dose-response curves for the 6 classical PDAC cell lines treated with different concentrations of gemcitabine (A) or phenformin (B) for 72 h. Live cells are indicated as a percentage of the control (vehicle treated). Data are means of triplicates ± SEMs. Data are representative of 3 independent experiments. The 0.5 mM concentration of phenformin is highlighted by a vertical dotted line in (B). The IC50 of phenformin was calculated and is shown on the right of the dose-response curve. (C) Representative dose-response curves for the 6 PDAC cell lines treated with low concentrations of gemcitabine alone (blue curves) and gemcitabine in combination with 0.5 mM phenformin (red curves) for 72 h. Cell viability is indicated as a percentage of the control (vehicle treated). Data are means of triplicates ± SEMs. (D) Representative dose-response curves for 6 primary PDAC cancer cells derived from PDX, 3 high OXPHOS (27, 74, and 84) and 3 low OXPHOS (22, 32, and 85). Cells were treated for 72 h with low concentrations of gemcitabine alone (blue curves) and in combination with 0.5 mM phenformin (red curves). Cell viability is indicated as the percentage of the control (vehicle treated). Data are means of triplicates ± SEMs. See also Figures S7 and S8.CC BY-NC-ND · PubMed Central
Figure 5 OXPHOS Shift Experiments Demonstrating That Gemcitabine Sensitivity Is a Feature of OXPHOS Low Cells (A) Panc-1 cells shift from high OXPHOS to low OXPHOS by treatment with tigecycline (Tig) enhances gemcitabine (Gem) cytotoxicity efficacy. Cell viability was monitored after 72 h of treatment with or without Gem (Left: 1 nM; right: 4 nM) and Tig (50 μM). Live cells are indicated as a percentage of the control (vehicle treated). Data are means of triplicates ± SEMs (∗p < 0.05, ∗∗p < 0.01, and ∗∗∗, p < 0.001; symbol over the bar, versus non-treated control; ns, not significant). Data are representative of 3 independent experiments. (B) MIA PaCa-2 and BxPC-3 cells shift from low OXPHOS to high OXPHOS by culture in galactose instead of glucose induces Gem resistance. Cell viability was monitored after 72 h of treatment with Gem (4 nM). Live cells are indicated as a percentage of the control (vehicle treated). Data are means of triplicates ± SEMs (∗∗∗p < 0.001 versus non-treated). Data are representative of 3 independent experiments.
Figure 5 OXPHOS Shift Experiments Demonstrating That Gemcitabine Sensitivity Is a Feature of OXPHOS Low Cells (A) Panc-1 cells shift from high OXPHOS to low OXPHOS by treatment with tigecycline (Tig) enhances gemcitabine (Gem) cytotoxicity efficacy. Cell viability was monitored after 72 h of treatment with or without Gem (Left: 1 nM; right: 4 nM) and Tig (50 μM). Live cells are indicated as a percentage of the control (vehicle treated). Data are means of triplicates ± SEMs (∗p < 0.05, ∗∗p < 0.01, and ∗∗∗, p < 0.001; symbol over the bar, versus non-treated control; ns, not significant). Data are representative of 3 independent experiments. (B) MIA PaCa-2 and BxPC-3 cells shift from low OXPHOS to high OXPHOS by culture in galactose instead of glucose induces Gem resistance. Cell viability was monitored after 72 h of treatment with Gem (4 nM). Live cells are indicated as a percentage of the control (vehicle treated). Data are means of triplicates ± SEMs (∗∗∗p < 0.001 versus non-treated). Data are representative of 3 independent experiments.CC BY-NC-ND · PubMed Central
Figure 6 Targeting Mitochondrial Respiratory Complex I with Phenformin Enhances Gemcitabine Antitumoral Activity in High OXPHOS Tumors in 2 Preclinical Mouse Models (A–C) Orthotopic xenografts. (A) Experimental schematic representation. One or 2 million MIA PaCa-2 and Panc-1 cells, respectively, were surgically implanted into the pancreas of 6-week-old female Swiss nude mice. The presence of a pancreatic tumor was confirmed by exploratory laparotomy at day 16 (MIA PaCa-2) or day 33 (Panc-1). After surgery recovery, treatments were started and lasted 4 weeks. (B) Representative gross photographs of pancreatic tumors for each treatment category. (C) Weight of orthotopic xenografts. Vehicle (control, n = 6); gemcitabine alone (Gem, n = 5 for MIA-PaCa-2 and n = 9 for Panc-1); combo gemcitabine + phenformin (Gem + Phen, n = 8 for MIA-PaCa-2 and n = 11 for Panc-1); and phenformin alone (Phen, n = 5). The mean in each group is shown as a horizontal line. p values were calculated from the Mann-Whitney test. ∗p < 0.05, ∗∗p < 0.01, and ∗∗∗p < 0.001. (D and E) Orthotopic syngeneic allografts. (D) Experimental scheme. One million KPC luc2 cells were intraperitoneally injected into 6-week-old female C57BL/6 mice. The presence of a pancreatic tumor was confirmed by bioluminescence (day 10), and the treatments were started at day 11 for 6 days. (E) Weight of orthotopic allografts. Vehicle (control, n = 6); gemcitabine alone (Gem, n = 5); combo gemcitabine + phenformin (Gem + Phen, n = 6); and phenformin alone (Phen, n = 6). The mean in each group is shown as a horizontal line. p values were calculated from the Mann-Whitney test. ∗p < 0.05 and ∗∗p < 0.01. See also Figure S9.
Figure 6 Targeting Mitochondrial Respiratory Complex I with Phenformin Enhances Gemcitabine Antitumoral Activity in High OXPHOS Tumors in 2 Preclinical Mouse Models (A–C) Orthotopic xenografts. (A) Experimental schematic representation. One or 2 million MIA PaCa-2 and Panc-1 cells, respectively, were surgically implanted into the pancreas of 6-week-old female Swiss nude mice. The presence of a pancreatic tumor was confirmed by exploratory laparotomy at day 16 (MIA PaCa-2) or day 33 (Panc-1). After surgery recovery, treatments were started and lasted 4 weeks. (B) Representative gross photographs of pancreatic tumors for each treatment category. (C) Weight of orthotopic xenografts. Vehicle (control, n = 6); gemcitabine alone (Gem, n = 5 for MIA-PaCa-2 and n = 9 for Panc-1); combo gemcitabine + phenformin (Gem + Phen, n = 8 for MIA-PaCa-2 and n = 11 for Panc-1); and phenformin alone (Phen, n = 5). The mean in each group is shown as a horizontal line. p values were calculated from the Mann-Whitney test. ∗p < 0.05, ∗∗p < 0.01, and ∗∗∗p < 0.001. (D and E) Orthotopic syngeneic allografts. (D) Experimental scheme. One million KPC luc2 cells were intraperitoneally injected into 6-week-old female C57BL/6 mice. The presence of a pancreatic tumor was confirmed by bioluminescence (day 10), and the treatments were started at day 11 for 6 days. (E) Weight of orthotopic allografts. Vehicle (control, n = 6); gemcitabine alone (Gem, n = 5); combo gemcitabine + phenformin (Gem + Phen, n = 6); and phenformin alone (Phen, n = 6). The mean in each group is shown as a horizontal line. p values were calculated from the Mann-Whitney test. ∗p < 0.05 and ∗∗p < 0.01. See also Figure S9.CC BY-NC-ND · PubMed Central

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Metadata

Authors
Masoud, R., Reyes-Castellanos, G., Lac, S., Garcia, J., Dou, S., Shintu, L., Abdel Hadi, N., Gicquel, T., El Kaoutari, A., Diémé, B., Tranchida, F., Cormareche, L., Borge, L., Gayet, O., Pasquier, E., Dusetti, N., Iovanna, J., & Carrier, A.
Affiliations
Centre National de la Recherche Scientifique (FR)
Corresponding author
  • Masoud, Rawand
  • Carrier, Alice
ORCID
Venue
Cell Reports Medicine
Publisher
Elsevier BV
Published
2020-11
Volume
1
Issue
8
Pages
100143
ISSN
2666-3791 (ISSN-L)
DOI
10.1016/j.xcrm.2020.100143
PMC
PMC7691450
OpenAlex
W3101012847
Cited by
175
References
47
Citations by year
2026: 14 · 2025: 35 · 2024: 49 · 2023: 27 · 2022: 27 · 2021: 23
FWCI
6.93
Type
journal article
Language
en
Open access
Licence
Locations
  • Cell Reports Medicine (publishedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • HAL AMU (submittedVersion, cc-by-nc-nd)
Funders
  • Institut National de la Santé et de la Recherche Médicale
  • Centre National de la Recherche Scientifique
  • Institut National Du Cancer
  • Fondation ARC pour la Recherche sur le Cancer (PJA 20151203544)
  • La Ligue Nationale contre le Cancer
  • DGOS
  • Fondation Amidex
  • Fondation de France
  • Canceropôle Provence-Alpes-Côte d’Azur
  • Fédération GEFLUC
  • Fondation pour la Recherche Médicale
  • CONACYT (339091/471717)
  • IMODI
  • Association Azm et Saadé
  • Agence Nationale de la Recherche
  • Canceropôle PACA
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
  • Health Sciences › Medicine › Oncology › Pancreatic and Hepatic Oncology Research
Keywords
pancreatic ductal adenocarcinoma, mitochondrial complex I, oxidative phosphorylation, chemoresistance, phenformin, gemcitabine, combination chemotherapy, tumor metabolic heterogeneity, mitochondrial respiration, synergistic drug combination, patient stratification
MeSH terms
PC-3 Cells, Gemcitabine, Animals, Deoxycytidine, Female, Humans, Male, Mice, Inbred C57BL, Mice, Nude, Mitochondria, Oxidative Phosphorylation, Pancreatic Neoplasms, Phenformin, Drug Resistance, Neoplasm, Cell Respiration, Carcinoma, Pancreatic Ductal, Xenograft Model Antitumor Assays, Electron Transport Complex I, Cell Line, Tumor, Cell Proliferation, Mice

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