Metformin induced lactic acidosis impaired response of cancer cells towards paclitaxel and doxorubicin: Role of monocarboxylate transporter

Singh, Shivendra V.; Chaube, Balkrishna; Mayengbam, Shyamananda Singh; Singh, Abhijeet; Malvi, Parmanand; Mohammad, Naoshad; Deb, Ankita; Bhat, Manoj Kumar

doi:10.1016/j.bbadis.2020.166011

Cited by 19 publications

(17 citation statements)

References 45 publications

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“…The results of metabolomic analysis showed that metformin could elevate lactate levels [ 35 ]. A recent study demonstrated that excessive lactate could lower anti-tumor efficacy of chemotherapeutic agents such as doxorubicin and paclitaxel [ 36 ]. Therefore, the production of plethoric lactate may be a key factor to trigger the low anti-tumor efficacy of metformin.…”

Section: Discussionmentioning

confidence: 99%

Dual Blockade of Lactate/GPR81 and PD-1/PD-L1 Pathways Enhances the Anti-Tumor Effects of Metformin

et al. 2021

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Metformin is a widely used antidiabetic drug for cancer prevention and treatment. However, the overproduction of lactic acid and its inefficiency in cancer therapy limit its application. Here, we demonstrate the synergistic effects of the lactate/GPR81 blockade (3-hydroxy-butyrate, 3-OBA) and metformin on inhibiting cancer cells growth in vitro. Simultaneously, this combination could inhibit glycolysis and OXPHOS metabolism, as well as inhibiting tumor growth and reducing serum lactate levels in tumor-bearing mice. Interestingly, we observed that this combination could enhance the functions of Jurkat cells in vitro and CD8+ T cells in vivo. In addition, considering that 3-OBA could recover the inhibitory effects of metformin on PD-1 expression, we further determined the dual blockade effects of PD-1/PD-L1 and lactate/GPR81 on the antitumor activity of metformin. Our results suggested that this dual blockade strategy could remarkably enhance the anti-tumor effects of metformin, or even lead to tumor regression. In conclusion, our study has proposed a novel and robust strategy for a future application of metformin in cancer treatment.

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Section: Discussionmentioning

confidence: 99%

Dual Blockade of Lactate/GPR81 and PD-1/PD-L1 Pathways Enhances the Anti-Tumor Effects of Metformin

et al. 2021

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“…At the same time, the effects of metformin in this study depended on the use of a high drug dose, which affected other experimental reagents and made measurements challenging. We suspect that these changes in experimental reagents may have been related to cellular acidosis, based on the side effect of lactic acidosis observed during the clinical application of metformin [ 36 , 37 ]. Notably, we excluded metformin from experiments other than those shown in Figure 4 , Figure 5 and Figure 6 because those findings strongly implied that the effects of 1,5-AF were similar to those of metformin; this is consistent with a published approach [ 22 ].…”

Section: Discussionmentioning

confidence: 99%

1,5-Anhydro-D-fructose Protects against Rotenone-Induced Neuronal Damage In Vitro through Mitochondrial Biogenesis

Kasamo

Kikuchi

Yamakuchi

et al. 2021

IJMS

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Mitochondrial functional abnormalities or quantitative decreases are considered to be one of the most plausible pathogenic mechanisms of Parkinson’s disease (PD). Thus, mitochondrial complex inhibitors are often used for the development of experimental PD. In this study, we used rotenone to create in vitro cell models of PD, then used these models to investigate the effects of 1,5-anhydro-D-fructose (1,5-AF), a monosaccharide with protective effects against a range of cytotoxic substances. Subsequently, we investigated the possible mechanisms of these protective effects in PC12 cells. The protection of 1,5-AF against rotenone-induced cytotoxicity was confirmed by increased cell viability and longer dendritic lengths in PC12 and primary neuronal cells. Furthermore, in rotenone-treated PC12 cells, 1,5-AF upregulated peroxisome proliferator-activated receptor-γ coactivator 1α (PGC-1α) expression and enhanced its deacetylation, while increasing AMP-activated protein kinase (AMPK) phosphorylation. 1,5-AF treatment also increased mitochondrial activity in these cells. Moreover, PGC-1α silencing inhibited the cytoprotective and mitochondrial biogenic effects of 1,5-AF in PC12 cells. Therefore, 1,5-AF may activate PGC-1α through AMPK activation, thus leading to mitochondrial biogenic and cytoprotective effects. Together, our results suggest that 1,5-AF has therapeutic potential for development as a treatment for PD.

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“…Another study has shown that BC chemotherapies, such as paclitaxel and doxorubicin, have a lower efficacy in diabetic patients under metformin treatment as a large amount of lactate produced is pumped out of cells by MCT4, hence inducing extracellular acidosis, which inhibits doxorubicin’s uptake. MCT4 inhibitors can potentially improve chemotherapy response in DM-associated BC patients by regulating the extracellular pH [ 15 ].…”

Section: Mrs Targeting Glucose Metabolismmentioning

confidence: 99%

Potential Therapies Targeting the Metabolic Reprogramming of Diabetes-Associated Breast Cancer

Shum

Vadgama

et al. 2023

JPM

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In recent years, diabetes-associated breast cancer has become a significant clinical challenge. Diabetes is not only a risk factor for breast cancer but also worsens its prognosis. Patients with diabetes usually show hyperglycemia and hyperinsulinemia, which are accompanied by different glucose, protein, and lipid metabolism disorders. Metabolic abnormalities observed in diabetes can induce the occurrence and development of breast cancer. The changes in substrate availability and hormone environment not only create a favorable metabolic environment for tumorigenesis but also induce metabolic reprogramming events required for breast cancer cell transformation. Metabolic reprogramming is the basis for the development, swift proliferation, and survival of cancer cells. Metabolism must also be reprogrammed to support the energy requirements of the biosynthetic processes in cancer cells. In addition, metabolic reprogramming is essential to enable cancer cells to overcome apoptosis signals and promote invasion and metastasis. This review aims to describe the major metabolic changes in diabetes and outline how cancer cells can use cellular metabolic changes to drive abnormal growth and proliferation. We will specifically examine the mechanism of metabolic reprogramming by which diabetes may promote the development of breast cancer, focusing on the role of glucose metabolism, amino acid metabolism, and lipid metabolism in this process and potential therapeutic targets. Although diabetes-associated breast cancer has always been a common health problem, research focused on finding treatments suitable for the specific needs of patients with concurrent conditions is still limited. Most studies are still currently in the pre-clinical stage and mainly focus on reprogramming the glucose metabolism. More research targeting the amino acid and lipid metabolism is needed.

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Metformin induced lactic acidosis impaired response of cancer cells towards paclitaxel and doxorubicin: Role of monocarboxylate transporter

Cited by 19 publications

References 45 publications

Dual Blockade of Lactate/GPR81 and PD-1/PD-L1 Pathways Enhances the Anti-Tumor Effects of Metformin

Dual Blockade of Lactate/GPR81 and PD-1/PD-L1 Pathways Enhances the Anti-Tumor Effects of Metformin

1,5-Anhydro-D-fructose Protects against Rotenone-Induced Neuronal Damage In Vitro through Mitochondrial Biogenesis

Potential Therapies Targeting the Metabolic Reprogramming of Diabetes-Associated Breast Cancer

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