Combining metformin with lactate transport inhibitors as a treatment modality for cancer - recommendation proposal

Benjamin, Don; Hall, Michael N.

doi:10.3389/fonc.2022.1034397

Cited by 7 publications

(2 citation statements)

References 18 publications

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“…In this case, VB124, an MCT4 inhibitor, had antitumor effect, and the combination of AZD3965 and VB124 sensitized the killing by metformin 31 . Consequently, the simultaneous inhibition of MCTs and mitochondrial respiration has strong fatal effects against tumor cells 32 . This study revealed that the classical MCTs non-selective inhibitor CHC suppressed the viability of A549 cells.…”

Section: Discussionmentioning

confidence: 99%

Monocarboxylate transporter 4 involves in energy metabolism and drug sensitivity in hypoxia

Yamaguchi

Mukai

Sakuma

et al. 2023

Sci Rep

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Metabolic reprogramming of cancer cells is a potential target for cancer therapy. It is also known that a hypoxic environment, one of the tumor microenvironments, can alter the energy metabolism from oxidative phosphorylation to glycolysis. However, the relationship between hypoxia and drug sensitivity, which targets energy metabolism, is not well known. In this study, A549 cells, a cell line derived from lung adenocarcinoma, were evaluated under normoxia and hypoxia for the sensitivity of reagents targeting oxidative phosphorylation (metformin) and glycolysis (α-cyano-4-hydroxycinnamic acid [CHC]). The results showed that a hypoxic environment increased the expression levels of monocarboxylate transporter (MCT) 4 and hypoxia-induced factor-1α (HIF-1α), whereas MCT1 and MCT2 expression did not vary between normoxia and hypoxia. Furthermore, the evaluation of the ATP production ratio indicated that glycolysis was enhanced under hypoxic conditions. It was then found that the sensitivity to metformin decreased while that to CHC increased under hypoxia. To elucidate this mechanism, MCT4 and HIF-1α were knocked down and the expression level of MCT4 was significantly decreased under both conditions. In contrast, the expression of HIF-1α was decreased by HIF-1α knockdown and increased by MCT4 knockdown. In addition, changes in metformin and CHC sensitivity under hypoxia were eliminated by the knockdown of MCT4 and HIF-1α, suggesting that MCT4 is involved in the phenomenon described above. In conclusion, it was shown that the sensitivity of reagents targeting energy metabolism is dependent on their microenvironment. As MCT4 is involved in some of these mechanisms, we hypothesized that MCT4 could be an important target molecule for cancer therapy.

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Section: Discussionmentioning

confidence: 99%

Monocarboxylate transporter 4 involves in energy metabolism and drug sensitivity in hypoxia

Yamaguchi

Mukai

Sakuma

et al. 2023

Sci Rep

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“…In 2016, one of us (Koltai T) proposed the double approach of increasing intracellular lactate production by inhibiting complex I in the electron transport chain, with metformin and simultaneously inhibiting lactate extrusion [ 197 ]. This theoretical idea was further developed by other authors [ 198 ] and was proposed by Benjamin and Hall [ 199 ] to be used with AZD3965 acting as a lactic acid extrusion inhibitor. By itself, to have a significant effect AZD3965 may require doses that are toxic, and results are poor.…”

Section: Mct Inhibitorsmentioning

confidence: 99%

Exploring monocarboxylate transporter inhibition for cancer treatment

Koltai,

Fliegel

2024

Exploration of Targeted Anti-Tumor Therapy

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Cells are separated from the environment by a lipid bilayer membrane that is relatively impermeable to solutes. The transport of ions and small molecules across this membrane is an essential process in cell biology and metabolism. Monocarboxylate transporters (MCTs) belong to a vast family of solute carriers (SLCs) that facilitate the transport of certain hydrophylic small compounds through the bilipid cell membrane. The existence of 446 genes that code for SLCs is the best evidence of their importance. In-depth research on MCTs is quite recent and probably promoted by their role in cancer development and progression. Importantly, it has recently been realized that these transporters represent an interesting target for cancer treatment. The search for clinically useful monocarboxylate inhibitors is an even more recent field. There is limited pre-clinical and clinical experience with new inhibitors and their precise mechanism of action is still under investigation. What is common to all of them is the inhibition of lactate transport. This review discusses the structure and function of MCTs, their participation in cancer, and old and newly developed inhibitors. Some suggestions on how to improve their anticancer effects are also discussed.

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Biophysical Approach to Understand Life and Cancer

Aykan

2024

Aging and Cancer

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BackgroundFrom the perspective of biology, the characteristics of life can be categorized as cellular organizations, homeostasis, metabolism, growth, reproduction and heredity, response to stimuli and adaptation to the environment. From the perspective of physics, living organisms are highly ordered, complex, thermodynamically open systems; they are in non‐equilibrium phase. According to the second law of thermodynamics, every system in the universe is going to the disorder spontaneously. Maximum entropy signifies a thermodynamic equilibrium which means the death. Today, cancer is a major global health problem and despite the explosive development of our knowledge about the carcinogenesis the “war on cancer” has not yet been won.AimsTo examine life and cancer together based on current biophysical approach and to shed light on new paradigms.Materials & MethodsA systematic literature search for publications on a thermodynamic approach to understand life and cancer was conducted in PubMed without language restrictions. The reference lists of identified studies were also used as additional knowledge.ResultsLiving organisms exchange entropy and they gain information from the external environment. Information can be stored as memory. Life is a category of emergence like art composed from correct modules. On the contrary, cancer is the emergence of a disease formed by incorrect modules. Cancer is a chaotic disease at least for a limited period and cannot arise from healthy functional tissue units. Chaos of the lower level may be associated with the entropy increase of upper level.ConclusionsBiologic chaos control is possible.

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Combining metformin with lactate transport inhibitors as a treatment modality for cancer - recommendation proposal

Cited by 7 publications

References 18 publications

Monocarboxylate transporter 4 involves in energy metabolism and drug sensitivity in hypoxia

Monocarboxylate transporter 4 involves in energy metabolism and drug sensitivity in hypoxia

Exploring monocarboxylate transporter inhibition for cancer treatment

Biophysical Approach to Understand Life and Cancer

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