Diclofenac and metformin synergistic dose dependent inhibition of hamster fibrosarcoma, rescued with mebendazole

Popović, Dušica J.; Popović, Kosta J.; Miljković, Dejan; Popović, Jovan K.; Lalošević, Dušan; Poša, Mihalj; Dolićanin, Zana; Čapo, Ivan

doi:10.1016/j.biopha.2023.115528

Cited by 3 publications

(1 citation statement)

References 67 publications

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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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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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Enhanced Anti‐inflammatory Effects of Diclofenac Delivered Orally via Polyvinylpyrrolidone K30/Silk Fibroin Nanoparticles in a Murine Model of Carrageenan‐Induced Paw Edema

Di,

Ha,

Nguyen

et al. 2024

ChemMedChem

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Diclofenac has a relatively low oral bioavailability (50‐60%) and is quickly metabolized with a half‐life of less than 1 h. Therefore, the oral therapeutic effect of diclofenac is not optimal. This research developed polyvinylpyrrolidone K30‐functionalized silk fibroin nanoparticles as an effective delivery system for diclofenac (FNPs‐PVP‐DC). The FNPs‐DC and FNPs‐PVP‐DC were formulated by two methods of adsorption and solvent exchange. Depending on the formulation factors, the obtained particles exhibited different properties of nano‐scale sizes (400‐800 nm), narrow size distribution, negatively charged surfaces (‐17 to ‐19 mV), high PVP K30 incorporation (23%‐50%), pHpzc of ~6.6, and appropriate chemical interactions. Interestingly, particles formulated by the adsorption method showed low drug encapsulation efficiencies of < 15%, whereas the solvent exchange method yielded moderate results of ~40%. The FNPs‐DC possessed aggregated patterns, while the FNPs‐PVP‐DC were more uniformly distributed. All formulations limited diclofenac release (< 20%) under gastric conditions and sustained its release in the intestinal environment. In in‐vivo carrageenan‐induced paw edema mice model, the FNPs‐PVP‐DC demonstrated a 20‐30% higher anti‐inflammatory effect and a faster onset of action (within 1 h) compared to pure diclofenac at the same dose (5 mg/kg). These findings suggest that FNPs‐PVP‐DC have promising potential as novel oral anti‐inflammatory products.

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Effects of metformin and its combinations with other repurposed drugs on fibrosarcoma in hamsters

Popovic,

Lalosevic

et al. 2024

Srp Arh Celok Lek

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Introduction/Objective. Many drugs registered for various other indications can act selectively on tumor receptors, signaling pathways, metabolic processes, bioenergetic factors, enzymes, proteins and genes that regulate tumor proliferation, apoptosis and neoangiogenesis without affecting these activities in healthy cells. Introduction of new drugs is a very long, complex and expensive process of research. Detecting an anticancer effect in drugs already registered for other indications and forming their combinations may directly reduce the time and cost of such research. Methods. Anticancer efficacy of metformin and its combinations with caffeine, itraconazole and nitroglycerin was tested on fibrosarcoma experimentally induced by BHK21/C13 cells in Syrian golden hamsters (six animals per group, randomly allocated to control and experimental groups, doses equivalent to usual human doses). After animal sacrifice, tumors were excised and their size, biophysical characteristics, histology and immunohistochemistry were assessed. Blood samples were collected for hematological and biochemical analyses and the main organs were toxicologically analyzed. Statistical significance was determined by one-way ANOVA followed by the Student-Newman-Keuls post hoc test. Results. Two-drug combinations of metformin with caffeine or itraconazole or nitroglycerin showed significant antitumor effects on hamster fibrosarcoma compared to control, regarding all tested tumor parameters (p < 0.05) without toxicity. Conclusion. Administration of metformin in combination with caffeine or itraconazole or nitroglycerin might be an effective and safe approach in novel nontoxic adjuvant anticancer treatment.

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Diclofenac and metformin synergistic dose dependent inhibition of hamster fibrosarcoma, rescued with mebendazole

Cited by 3 publications

References 67 publications

Exploring monocarboxylate transporter inhibition for cancer treatment

Exploring monocarboxylate transporter inhibition for cancer treatment

Enhanced Anti‐inflammatory Effects of Diclofenac Delivered Orally via Polyvinylpyrrolidone K30/Silk Fibroin Nanoparticles in a Murine Model of Carrageenan‐Induced Paw Edema

Effects of metformin and its combinations with other repurposed drugs on fibrosarcoma in hamsters

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