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Physicochemical and pathohistological changes in experimental fibrosarcoma tumors of hamsters treated with metformin
Kosta J Popović1, Dušica J Popović2, Dejan Miljković2
1Department of Pharmacy, Faculty of Medicine, University of Novi Sad, 21000 Novi Sad, Republic of Serbia.
Abstract:
The anticancer effects of metformin (an antihyperglycaemic agent) and itraconazole (an antifungal agent), which are established non-oncologic drugs, were investigated in the present study. The weight, diameter, volume, density, surface, surface to volume ratio and immunohistochemistry of experimental fibrosarcoma tumors were investigated in hamsters treated with metformin and itraconazole. Briefly, the hamsters were injected with BHK-21/C13 cells in order to induce fibrosarcoma, and the animals were treated daily with metformin, itraconazole or a combination of the two drugs. Subsequently, blood samples were obtained for biochemical analyses and the tumors were excised, weighed and measured. The tumor samples were pathohistologically and immunohistochemically assessed for proliferation marker protein Ki-67, hematopoietic progenitor cell antigen CD34, cytochrome c oxidase subunit 4 (COX4), glucose transporter 1 (GLUT1) and inducible nitric oxide synthase (iNOS), and vital organs were toxicologically tested. Ki-67-positivity and cytoplasmic marker (CD34, COX4, GLUT1, iNOS) immunoexpression in the tumor samples were quantified. The results revealed that the combination of metformin and itraconazole significantly altered the physicochemical and pathohistological characteristics of the hamster fibrosarcoma tumors, including absolute and relative weight, volume, density, length, surface area, surface to volume ratio, Ki-67-positivity and the immunoexpression of cytoplasmic markers, without indications of toxicity. Furthermore, metformin with itraconazole demonstrated antiproliferative functions in cervical carcinoma HeLa, colon carcinoma HT-29, lung carcinoma A549 and fibrosarcoma BHK-21/C13 cells, with markedly lower cytotoxicity in the normal fetal lung MRC-5 cells. In conclusion, the administration of metformin in combination with itraconazole may inhibit the growth of fibrosarcoma tumors in vivo and the proliferation of various malignant cell lines in vitro, suggesting that this may be an effective and safe approach as a nontoxic anticancer adjuvant and relapse prevention therapy.
Insights
Metformin and itraconazole combination therapy showed significant anticancer effects against fibrosarcoma tumors in hamsters. This non-oncologic drug combination also inhibited various cancer cell lines in vitro with low toxicity.
Area of Science:
- Oncology
- Pharmacology
- Experimental Pathology
Background:
- Established non-oncologic drugs, metformin (antihyperglycaemic) and itraconazole (antifungal), possess potential anticancer properties.
- Investigating repurposed drugs offers novel therapeutic avenues for cancer treatment.
Purpose of the Study:
- To evaluate the anticancer effects of metformin and itraconazole, alone and in combination, on experimental fibrosarcoma tumors in hamsters.
- To assess the antiproliferative activity and cytotoxicity of this drug combination on various human cancer cell lines.
Main Methods:
- Induction of fibrosarcoma in hamsters followed by daily treatment with metformin, itraconazole, or their combination.
- Assessment of tumor physicochemical and pathohistological characteristics, including Ki-67 and cytoplasmic marker immunoexpression.
- In vitro antiproliferative and cytotoxicity assays using cervical, colon, lung carcinoma, fibrosarcoma, and normal fetal lung cell lines.
Main Results:
- The combination of metformin and itraconazole significantly altered fibrosarcoma tumor characteristics (weight, volume, Ki-67, marker expression) without inducing toxicity.
- Metformin and itraconazole demonstrated significant antiproliferative effects on multiple cancer cell lines (HeLa, HT-29, A549, BHK-21/C13).
- The drug combination exhibited markedly lower cytotoxicity against normal fetal lung MRC-5 cells.
Conclusions:
- Metformin and itraconazole combination therapy effectively inhibits fibrosarcoma tumor growth in vivo and cancer cell proliferation in vitro.
- This combination represents a potentially safe and effective non-toxic anticancer adjuvant and relapse prevention strategy.
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