• ischemia-reperfusion injury
• kidney transplant
• metformin

• PROGETTi PICCOLI MEDI GRANDI 2022 DM 737 Sapienza University

• BMI1
• alexidine
• apoptosis
• chronic myeloid leukemia
• leukemic stem/progenitor cells
• oxidative metabolism

• Antimicrobial
• Antioxidant
• Antiviral
• Leukemia
• Lymphoma
• Seed coat pea

• Minia University

• AMPK
• leukemia
• lymphoma
• metformin
• myeloma

• Humans
• Metformin/pharmacology
• AMP-Activated Protein Kinases/metabolism
• Diabetes Mellitus, Type 2/drug therapy
• Neoplasms/drug therapy
• Hematologic Neoplasms

• ZDXKB2016020 Government of Jiangsu Province

• cannabis
• circulating tumor DNA
• hyperthermia
• integrative oncology
• naturopathic oncology
• prospective cancer outcomes study
• psychedelic therapy
• psychoneuroendocrineimmunology

• Humans
• Integrative Oncology
• Anniversaries and Special Events
• Medical Oncology
• Neoplasms/therapy
• Brain Neoplasms
• North America
• Tumor Microenvironment

This investigation was conducted to analyze and evaluate the impact of Chinese herbal medicine on glucolipid metabolism in women with polycystic ovary syndrome (PCOS).

We used manual and computer-aided search methods, and the search scopes included Chinese databases (China National Knowledge Infrastructure, Wanfang, the China Science and Technology Journal Database, and the Chinese Biomedical Literature Database) and English databases (PubMed, Embase, Web of Science, and the Cochrane Library). We searched these eight databases for randomized controlled trials investigating the effects of Chinese herbal medicine on glucolipid metabolism in women with PCOS, with the retrieval deadline being June 2021. Two reviewers screened, selected, and extracted data and verified the results independently. The NoteExpress software was used to manage and screen the literature, the risk of bias assessment tool was used to evaluate the methodological quality of the included studies, and the RevMan 5.4 software was used for meta-analysis.

A total of 13 trials were included, including 825 patients with PCOS. Because the drugs used in the control group were different, we divided the results into two parts, with four trials using placebo and nine trials using metformin as the control. The results of the meta-analysis showed that fasting insulin (MD = −2.45, 95% CI = [−4.74, −0.17], P = 0.04), 2 h fasting plasma glucose (MD = −0.33, 95% CI = [−0.64, −0.02], P = 0.04), serum total cholesterol (MD = −0.38, 95% CI = [−0.58, −0.18], P = 0.0002), triglycerides (MD = −0.36, 95% CI = [−0.58, −0.14], P = 0.001), and low-density lipoprotein cholesterol (MD = −0.58, 95% CI = [−0.75, −0.41], P < 0.00001) were significantly improved in the Chinese herbal medicine group compared with the placebo group. In addition, compared with metformin, body mass index (MD = −1.04, 95% CI = [−1.55, −0.53], P < 0.0001), serum total cholesterol (MD = −0.27, 95% CI = [−0.46, −0.07] P = 0.007), and low-density lipoprotein cholesterol were significantly reduced (MD = −0.12, 95% CI = [−0.22, −0.02], P = 0.02) and high-density lipoprotein cholesterol (MD = 0.09, 95% CI = [0.02, 0.17], P = 0.01) was significantly improved after treatment with Chinese herbal medicine.

Compared with the placebo group, Chinese herbal medicine had positive effects on glucolipid metabolism in women with PCOS. Chinese herbal medicine had a positive effect on lipid metabolism when the control group was metformin, but no effect on glucose metabolism. These findings need to be verified in high-quality, large-sample, randomized controlled trials in the future.

Chemotherapy resistance is one of the major challenges in cancer treatment, including leukemia. A massive array of research is evaluating combinations of drugs directed against different intracellular signaling molecules to overcome cancer resistance, increase therapy effectiveness, and decrease its adverse effects. Combining chemicals with proven safety profiles, such as drugs already used in therapy and active substances isolated from natural sources, could potentially have superior effects compared to monotherapies. In this study, we evaluated the effects of metformin and thymoquinone (TQ) as monotherapy and combinatorial treatments in chronic myeloid leukemia (CML) cell lines sensitive and resistant to imatinib therapy. The effects were also evaluated in primary monocytic acute myeloid leukemia (AML) and chronic lymphocytic leukemia (CLL) cells. Both compounds induced a dose- and time-dependent decrease of viability and proliferation in tested cells. Metformin had similar IC₅₀ values in imatinib-sensitive and imatinib-resistant cell lines. IC₅₀ values of TQ were significantly higher in imatinib-resistant cells, but with a limited resistance index (2.4). Synergistic effects of combinatorial treatments were observed in all tested cell lines, as well as in primary cells. The strongest synergistic effects were observed in the inhibition of imatinib-resistant cell line proliferation. Metformin and TQ inhibited the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling and induced apoptosis in tested cell lines and primary cells. The enhanced effects of combinatorial treatments on the induction of apoptosis were more dominant in imatinib-resistant compared to imatinib-sensitive CML cells. Primary cells were more sensitive to combinatorial treatments compared to cell lines. A combination of 1.25 mM metformin and 0.625 µM TQ increased the levels of cleaved poly (ADP-ribose) polymerase (PARP), decreased the levels of proliferation regulatory proteins, and inhibited protein kinase B (Akt) and NF-κB signaling in primary CLL cells. This study demonstrates that combinatorial treatments of imatinib-resistant malignant clones with metformin and TQ by complementary intracellular multi-targeting represents a promising approach in future studies.

• AKT/mTOR signaling pathway
• Metformin
• leukemia
• lymphoma
• multiple myeloma

• National Health Insurance
• Taiwan
• diabetes mellitus
• leukemia
• metformin

• Diabetes Mellitus, Type 2/drug therapy
• Diabetes Mellitus, Type 2/epidemiology
• Female
• Humans
• Hypoglycemic Agents/adverse effects
• Leukemia/chemically induced
• Leukemia/epidemiology
• Male
• Metformin/adverse effects
• Middle Aged
• Propensity Score
• Proportional Hazards Models
• Risk Factors

• AXL
• Leukemia
• MERTK
• Metformin
• TYRO3

Chronic Myeloid Leukaemia is a myeloproliferative disorder driven by the t(9;22) chromosomal translocation coding for the chimeric protein BCR-ABL. CML treatment represents the paradigm of molecular therapy of cancer. Since the development of the tyrosine kinase inhibitor of the BCR-ABL kinase, the clinical approach to CML has dramatically changed, with a stunning improvement in the quality of life and response rates of patients. However, it remains clear that tyrosine kinase inhibitors (TKIs) are unable to target the most immature cellular component of CML, the CML stem cell. This review summarizes new insights into the mechanisms of resistance to TKIs.

• chronic myeloid leukaemia
• stem cells
• tyrosine kinase inhibitors

• AICAR
• AML
• AMPK
• differentiation
• mTOR
• metformin
• rapamycin.

• atorvastatin
• doxycycline
• glioblastoma
• mebendazole
• metabolic targeting
• metformin
• off-label
• pluralistic evidence

• Combined treatment
• Functional activities
• Human GM-MDMs
• LPS-activated GM-MDMs, metformin
• Selenium
• Sodium selenite

• AMP-activated protein kinase (AMPK)
• assisted reproduction techniques
• membranes
• mitochondria
• motility
• signaling
• spermatozoa
• stress

• AMP-Activated Protein Kinases/metabolism
• Animals
• Humans
• Male
• Membrane Potential, Mitochondrial/genetics
• Membrane Potential, Mitochondrial/physiology
• Semen/metabolism
• Signal Transduction/genetics
• Signal Transduction/physiology
• Sperm Motility/genetics
• Sperm Motility/physiology
• Spermatozoa/metabolism
• Spermatozoa/physiology

• metformin
• diabetes
• blood cancers
• myeloma
• leukemia
• lymphoma

• Body Mass Index
• Diabetes Mellitus, Type 2/complications
• Diabetes Mellitus, Type 2/drug therapy
• Humans
• Hypoglycemic Agents/adverse effects
• Hypoglycemic Agents/therapeutic use
• Insulin
• Leukemia/complications
• Leukemia/drug therapy
• Lymphoma/complications
• Lymphoma/drug therapy
• Metformin/adverse effects
• Metformin/therapeutic use
• Plasmacytoma/complications
• Plasmacytoma/drug therapy
• Risk Factors

AMP-activated kinase (AMPK), a protein that regulates energy balance and metabolism, has recently been identified in boar spermatozoa where regulates key functional sperm processes essential for fertilization. This work's aims are AMPK identification, intracellular localization, and their role in human spermatozoa function. Semen was obtained from healthy human donors. Sperm AMPK and phospho-Thr172-AMPK were analyzed by Western blotting and indirect immunofluorescence. High- and low-quality sperm populations were separated by a 40%–80% density gradient. Human spermatozoa motility was evaluated by an Integrated Semen Analysis System (ISAS) in the presence or absence of the AMPK inhibitor compound C (CC). AMPK is localized along the human spermatozoa, at the entire acrosome, midpiece and tail with variable intensity, whereas its active form, phospho-Thr172-AMPK, shows a prominent staining at the acrosome and sperm tail with a weaker staining in the midpiece and the postacrosomal region. Interestingly, spermatozoa bearing an excess residual cytoplasm show strong AMPK staining in this subcellular compartment. Both AMPK and phospho-Thr172-AMPK human spermatozoa contents exhibit important individual variations. Moreover, active AMPK is predominant in the high motility sperm population, where shows a stronger intensity compared with the low motility sperm population. Inhibition of AMPK activity in human spermatozoa by CC treatment leads to a significant reduction in any sperm motility parameter analyzed: percent of motile sperm, sperm velocities, progressivity, and other motility coefficients. This work identifies and points out AMPK as a new molecular mechanism involved in human spermatozoa motility. Further AMPK implications in the clinical efficiency of assisted reproduction and in other reproductive areas need to be studied.

• cancer
• cell cycle
• extracellular matrix
• growth
• microenvironment
• proliferation
• quiescence
• tissue architecture

Epidemiological studies have demonstrated that metformin could mitigate the progression of several tumors. Although it has been proved that metformin could cause demethylation of DNA and lead to up-regulation of some encoding genes and non-coding RNAs, there is little data about the effects of metformin on metastasis, and the interaction between metastasis and autophagy in human osteosarcoma cells. Here, we found miR-570-3p was significantly down-regulated in human metastatic osteosarcoma tissues but not in non-metastatic osteosarcoma tissues. Metformin attenuates the metastasis and autophagy in osteosarcoma. Interestingly, this autophagy favors osteosarcoma cells invasion. Moreover, reduction of metformin-induced inhibition of autophagy could reverse the invasion suppression in osteosarcoma. Mechanistically, metformin increases miR-570-3p by the demethylation of DNA, and the upregulation of miR-570-3p repressed the translation of its target, LCMR1 and ATG12. Our results, for the first time, presents evidence that the miR-570-3p-mediated suppression of LCMR1 and ATG12 is involved in the metformin-induced inhibition of metastasis in osteosarcoma cells.

The recurrent gain-of-function JAK2^V617F mutation confers growth factor-independent proliferation for hematopoietic cells and is a major contributor to the pathogenesis of myeloproliferative neoplasms (MPN). The lack of complete response in most patients treated with the JAK1/2 inhibitor ruxolitinib indicates the need for identifying novel therapeutic strategies. Metformin is a biguanide that exerts selective antineoplastic activity in hematological malignancies. In the present study, we investigate and compare effects of metformin and ruxolitinib alone and in combination on cell signaling and cellular functions in JAK2^V617F-positive cells. In JAK2^V617F-expressing cell lines, metformin treatment significantly reduced cell viability, cell proliferation, clonogenicity, and cellular oxygen consumption and delayed cell cycle progression. Metformin reduced cyclin D1 expression and RB, STAT3, STAT5, ERK1/2 and p70S6K phosphorylation. Metformin plus ruxolitinib demonstrated more intense reduction of cell viability and induction of apoptosis compared to monotherapy. Notably, metformin reduced Ba/F3 JAK2^V617F tumor burden and splenomegaly in Jak2^V617F knock-in-induced MPN mice and spontaneous erythroid colony formation in primary cells from polycythemia vera patients. In conclusion, metformin exerts multitarget antileukemia activity in MPN: downregulation of JAK2/STAT signaling and mitochondrial activity. Our exploratory study establishes novel molecular mechanisms of metformin and ruxolitinib action and provides insights for development of alternative/complementary therapeutic strategies for MPN.

• Jurkat cells
• PPARγ
• cell cycle arrest
• metformin
• proliferation
• rosiglitazone

• Biguanides/chemistry
• Biguanides/pharmacology
• Binding Sites
• Crystallization
• Escherichia coli/enzymology
• Escherichia coli/genetics
• Escherichia coli/metabolism
• Folic Acid Antagonists/chemistry
• Folic Acid Antagonists/pharmacology
• Hypoglycemic Agents/chemistry
• Hypoglycemic Agents/pharmacology
• Models, Molecular
• Molecular Structure
• Protein Conformation
• Structure-Activity Relationship
• Tetrahydrofolate Dehydrogenase/metabolism

• ZIA ES102645 Intramural NIH HHS
• R15 GM110669 NIGMS NIH HHS
• ZIA ES050111 Intramural NIH HHS
• ZIA ES102645-08 Intramural NIH HHS
• ZIA ES102645 NIEHS NIH HHS
• Z01 ES050111-19 Intramural NIH HHS
• ZIA ES050111 NIEHS NIH HHS

To evaluate whether metformin's cancer-related benefits reported in patients with solid tumors (ST) are also present in acute myeloid leukemia (AML) patients.

Baseline demographic and clinical history for all diabetes mellitus patients newly diagnosed with AML or cancer of the breast, ovary, prostate, gastrointestinal tract, lung, or kidney at Roswell Park Cancer Institute in Buffalo, NY (January 2003–December 2010, n = 924) was collected. Overall survival (OS) and disease-free survival (DFS) were assessed by Kaplan–Meier (KM) analysis and Cox proportional hazards regression (hazard ratio [HR]).

Baseline metformin use provided significant OS and DFS benefit in ST but not in AML (KM: P_ST-OS= 0.003; P_ST-DFS= 0.002; P_AML-OS= 0.961; P_AML-DFS= 0.943). AML median survival was slightly better with metformin use, but users derived no relapse benefit. In ST, metformin nonusers had shorter median survival, 57.7 versus 86 months, and poorer outcomes (HR_ST-OS= 1.33; P_ST-OS= 0.002; HR_ST-DFS= 1.32; P_ST-DFS= 0.002). These findings remained significant in age-adjusted models (HR_ST-OS= 1.21; P_ST-OS= 0.039; HR_ST-DFS= 1.23; P_ST-DFS= 0.02) but not fully adjusted models (HR_ST-OS= 0.96; P_ST-OS= 0.688; HR_ST-DFS= 1.0; P_ST-DFS= 0.94). Higher mortality was noted in AML patients taking insulin versus oral diabetes pharmacotherapy at baseline (HR_AML-OS= 2.03; P_AML-OS= 0.04).

Lack of metformin benefit in AML could be due to advanced age at cancer diagnosis. Metformin substitution with insulin before computed tomography scans with contrast – a frequent AML assessment practice – may also explain the lack of subsequent benefit despite taking metformin at baseline. A temporary metformin substitution is recommended by the package insert due to a possible drug interaction with the contrast dye. Our data suggest that metformin substitution was permanent in many patients. Nonetheless, the observed benefit in other malignancies warrants further investigation of metformin use in AML.

• Acute myeloid leukemia
• Metformin
• disease-free survival
• overall survival
• solid tumors

• Cancer
• Mitochondria
• biguanide
• metabolism
• metformin
• synthetic lethality
• syrosingopine

• Animals
• Cell Line, Tumor
• Drug Synergism
• Glycolysis
• Humans
• Metformin/pharmacology
• Mice
• Mice, Knockout
• Phenformin/pharmacology
• Phosphopyruvate Hydratase/chemistry
• Reserpine/analogs & derivatives
• Reserpine/pharmacology

• Cancer metabolism
• Glycolysis
• Leukemia
• Metformin
• Oxidative phosphorylation

Recent epidemiological studies showed that metformin, a widely used anti-diabetic drug might prevent certain cancers. Metformin also has an anti-proliferative effect in preclinical studies of both hematologic malignancies as well as solid cancers and clinical studies testing metformin as an anti-cancer drug are in progress. However, all cancer types do not respond to metformin with the same effectiveness or acquire resistance. To understand the mechanism of acquired resistance and possibly its mechanism of action as an anti-proliferative agent, we developed metformin resistant LNCaP prostate cancer cells. Metformin resistant LNCaP cells had an increased proliferation rate, increased migration and invasion ability as compared to the parental cells, and expressed markers of epithelial-mesenchymal transition (EMT). A detailed gene expression microarray comparing the resistant cells to the wild type cells revealed that Edil2, Ereg, Axl, Anax2, CD44 and Anax3 were the top up-regulated genes and calbindin 2 and TPTE (transmembrane phosphatase with tensin homology) and IGF1R were down regulated. We focused on Axl, a receptor tyrosine kinase that has been shown to be up regulated in several drug resistance cancers. Here, we show that the metformin resistant cell line as well as castrate resistant cell lines that over express Axl were more resistant to metformin, as well as to taxotere compared to androgen sensitive LNCaP and CWR22 cells that do not overexpress Axl. Forced overexpression of Axl in LNCaP cells decreased metformin and taxotere sensitivity and knockdown of Axl in resistant cells increased sensitivity to these drugs. Inhibition of Axl activity by R428, a small molecule Axl kinase inhibitor, sensitized metformin resistant cells that overexpressed Axl to metformin. Inhibitors of Axl may enhance tumor responses to metformin and other chemotherapy in cancers that over express Axl.

• Axl and drug resistance
• Axl receptor tyrosine kinase
• metformin
• prostate cancer

• BDNF
• Metformin
• NGF
• Neurotrophin 3
• Nrf2
• Water maze

Recent epidemiological studies indicate that the antidiabetic drug metformin has chemosensitizing and chemopreventive effects against carcinogenesis. Here, we demonstrate that metformin exerts varying degrees of antitumor activity against human leukemia cells, as reflected by differences in growth inhibition, apoptosis, and alterations to metabolic enzymes. In metformin-sensitive cells, autophagy was not induced but rather it blocked proliferation by means of arresting cells in the S and G2/M phases which was associated with the downregulation of cyclin A, cyclin B1, and cdc2, but not that of cyclin E. In 10E₁-CEM cells that overexpress Bcl-2 and are drug-resistant, the effect of metformin on proliferation was more pronounced, also inducing the activation of the caspases 3/7 and hence apoptosis. In all sensitive cells, metformin decreased the Δψ_m and it modified the expression of enzymes involved in energy metabolism: PKCε (PKCepsilon) and PKCδ (PKCdelta). In sensitive cells, metformin altered PKCε and PKCδ expression leading to a predominance of PKCε over PKCδ which implies a more glycolytic state. The opposite occurs in the nonresponsive cells. In conclusion, we provide new insights into the activity of metformin as an antitumoral agent in leukemia cells that could be related to its capability to modulate energy metabolism.

• AMPK
• cancer
• metformin
• prevention
• therapy

• Adriamycin
• Metformin
• Mice
• Transplantable tumor

• Animals
• Antibiotics, Antineoplastic/pharmacology
• Apoptosis/drug effects
• Disease Models, Animal
• Doxorubicin/pharmacology
• Hypoglycemic Agents/pharmacology
• Malondialdehyde/metabolism
• Metformin/pharmacology
• Mice, Inbred BALB C
• Neoplasms/drug therapy
• Tumor Necrosis Factor-alpha/metabolism

Metformin, a biguanide derivative, is the most commonly prescribed medication in the treatment of type 2 diabetes mellitus. More recently, the use of metformin has shown potential as a preventive and therapeutic agent for a broad spectrum of conditions, including liver disease and hepatic malignancies. In this systematic review, we critically analyze the literature behind the potential use of metformin across the spectrum of liver disease and malignancies. The PubMed and Ovid MEDLINE databases were searched from 2000 to March 2015, using a combination of relevant text words and MeSH terms: metformin and mammalian target of rapamycin, hepatitis B virus (HBV), hepatitis B virus (HCV), non-alcoholic fatty liver disease (NAFLD), hepatocellular carcinoma (HCC) or cholangiocarcinoma. The search results were evaluated for pertinence to the issue of metformin in liver disease as well as for quality of study design. Metformin has a number of biochemical effects that would suggest a benefit in treating chronic liver diseases, particularly in the context of insulin resistance and inflammation. However, the literature thus far does not support any independent therapeutic role in NAFLD or HCV. Nonetheless, there is Level III evidence for a chemopreventive role in patients with diabetes and chronic liver disease, with decreased incidence of HCC and cholangiocarcinoma. The use of metformin seems to be safe in patients with cirrhosis, and provides a survival benefit. Once hepatic malignancies are already established, metformin does not offer any therapeutic potential. In conclusion, there is insufficient evidence to recommend use of metformin in the adjunctive treatment of chronic liver diseases, including NAFLD and HCV. However, there is good evidence for a chemopreventive role against HCC among patients with diabetes and chronic liver disease, and metformin should be continued in patients even with cirrhosis to provide this benefit.

• Non-alcoholic fatty liver disease
• Metformin
• Chemoprevention
• Hepatocellular carcinoma
• Hepatitis C

• AUC, area under the curve
• HOMA-IR, homeostasis model assessment of insulin resistance
• HOMA-β, homeostasis model assessment of β-cell function
• LBW, body weight loss
• MHC-I, major histocompatibility complex class I
• NAL, nasal anal length
• VEGF, vascular endothelial growth factor.
• Walker 256 tumor
• adolescence
• antidiabetic
• early treatment
• metformin
• prevention
• tumor growth inhibition

• Carrier Proteins/metabolism
• Cell Proliferation
• Down-Regulation
• Enzyme Activation
• Glucose/metabolism
• Mechanistic Target of Rapamycin Complex 1
• Multiprotein Complexes/antagonists & inhibitors
• Multiprotein Complexes/metabolism
• Phosphorylation
• Protein Kinases/metabolism
• Protein Serine-Threonine Kinases/metabolism
• Saccharomyces cerevisiae/enzymology
• Saccharomyces cerevisiae/growth & development
• Saccharomyces cerevisiae/metabolism
• Saccharomyces cerevisiae Proteins/metabolism
• Signal Transduction
• TOR Serine-Threonine Kinases/antagonists & inhibitors
• TOR Serine-Threonine Kinases/metabolism

• R15 GM100376 NIGMS NIH HHS
• R15 GM100376-01 NIGMS NIH HHS

• metformin
• diabetes
• endothelium
• cardiovascular disease
• oxidative stress

• AMP-Activated Protein Kinases/biosynthesis
• Adenylyl Cyclases/metabolism
• Diabetes Mellitus, Type 2/drug therapy
• Diabetes Mellitus, Type 2/physiopathology
• Dose-Response Relationship, Drug
• Endothelium/metabolism
• Gluconeogenesis/drug effects
• Glucose Transporter Type 4/metabolism
• Glycation End Products, Advanced/metabolism
• Humans
• Metformin/pharmacokinetics
• Metformin/pharmacology
• Mitochondria/metabolism
• Neoplasms/drug therapy
• Neoplasms/physiopathology
• Protein Kinase C/metabolism
• Retrospective Studies
• Signal Transduction
• Sirtuins/metabolism
• TOR Serine-Threonine Kinases/biosynthesis
• Vascular Diseases/drug therapy
• Vascular Diseases/physiopathology

• T cells
• cancer
• immunometabolism
• metabolic targeting agents
• obesity

To establish the effect of low (11 mM) and high (55 mM) glucose concentrations (G11, G55) on Jurkat cells exposed to rotenone (ROT, a class 5 mitocan). We demonstrated that ROT induces apoptosis in Jurkat cells cultured in G11 by oxidative stress (OS) mechanism involving the generation of anion superoxide radical (O₂^∙−, 68%)/hydrogen peroxide (H₂O₂, 54%), activation of NF-κB (32%), p53 (25%), c-Jun (17%) transcription factors, and caspase-3 (28%), apoptosis-inducing factor (AIF, 36%) nuclei translocation, c-Jun N-terminal kinase (JNK) activation, and loss of mitochondria transmembrane potential (ΔΨ_m, 62%) leading to nuclei fragmentation (~10% and ~40% stage I-II fragmented nuclei, resp.). ROT induces massive cytoplasmic aggregates of DJ-1 (93%), and upregulation of Parkin compared to untreated cells, but no effect on PINK-1 protein was observed. Cell death marker detection and DJ-1 and Parkin expression were significantly reduced when cells were cultured in G55 plus ROT. Remarkably, metformin sensitized Jurkat cells against ROT in G55. Our results indicate that a high-glucose milieu promotes resistance against ROT/H₂O₂-induced apoptosis in Jurkat cells. Our data suggest that combined therapy by using mitochondria-targeted damaging compounds and regulation of glucose (e.g., metformin) can efficiently terminate leukemia cells via apoptosis in hyperglycemic conditions.