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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.

Purpose: To investigate the effect of mebendazole on an in vivo solid tumor model of fibrosarcoma in hamsters.Methods: 24 Syrian golden hamsters of both sexes with the approximate body weight of 100g were randomly distributed in 2 experimental and 2 control groups, with 6 animals in each group. BHK-21/C13 cells (2 x 106) in 1 mL Glasgow Minimum Essential Medium (GMEM) were injected subcutaneously into the back of each animal in 3 groups. The experimental groups were treated with mebendazole (460 mg/kg) via a gastric tube on a daily basis, immediately after tumor inoculation. In addition, one experimental group received deoxycholic acid 20 mg/kg once a day. After 2 weeks, when the tumors were approximately 1 - 2 cm in the control group, all the animals were sacrificed, and their blood collected for laboratory analysis. The tumors were excised, their weight and diameters measured, and the volumes calculated. The tumor samples were histopathologically assessed and the main organs toxicologically analyzed. Images were taken and processed by an imaging software, and Ki-67-positive cells in the tumor samples were quantified.Results: Mebendazole diminished tumor mitosis from 18.5 ± 3.02 to 13.5 ± 3.45 (p < 0.05), vasculature and tissue penetration, and increased necroses in tumor slices. Tumor volume and weight were insignificantly attenuated. Toxicity was not observed.Conclusion: Mebendazole might be an effective non-toxic agent in sarcoma therapy.Keywords: Mebendazole, Hamsters, BHK-21/C13 cells, Fibrosarcoma therapy, Tumor mitosis

Although clinical trials have not been completed, it has already been confirmed that mebendazole, a well-known anti-parasitic drug widely used in the tropical areas, inhibits cancer cell growth. Preclinical studies show that mebendazole notably impedes the growth of malignant and metastatic tumors such as osteosarcoma and soft tissue sarcoma, melanoma, carcinoma (lung, colorectal, breast, ovarian, hepatocellular and adrenocortical), acute myeloid leukaemia, glioblastoma multiforme and meduloblastoma. Mebendazole can induce the depolymerization of microtubules in neoplasms and newly formed vasculature, stopping tumor growth and neoangiogenesis, along with other proposed mechanisms of action.Keywords: Anthelmintic, Mebendazole, Cancer treatment, Antimicrotubullar effect, Antineoangiogenesis

We investigated the effect of nitroglycerin with metformin on fibrosarcoma in hamsters. Syrian golden hamsters of both sexes, weighing approximately 60 g, were randomly allocated to control and experimental groups, with 8 animals per group. In all groups, 2 × 106 BHK-21/C13 cells in 1 ml were injected subcutaneously into the animals’ backs. Peroral treatment carried out with nitroglycerin 25 mg/kg daily, or with metformin 500 mg/kg daily, or with a combination of nitroglycerin 25 mg/kg and metformin 500 mg/kg daily. Later validation experiments were conducted with double doses of the single therapy and additional rescue doses of mebendazole 460 mg/kg daily, via a gastric probe after tumor inoculation. After 2 weeks, when the tumors were approximately 2−3 cm in the control group, all animals were sacrificed. Blood samples were collected for hematological and biochemical analyses, the tumors were excised and weighed, and their diameters and volumes were measured. The tumor samples were pathohistologically and immunohistochemically assessed for proliferation marker protein Ki-67, proliferating cell nuclear antigen PCNA, hematopoietic progenitor cell antigen CD34, cluster of differentiation 31 (CD31), cytochrome c oxidase subunit 4 (COX4), mitochondria marker Cytochrome C, glucose transporter 1 (GLUT1) and inducible nitric oxide synthase (iNOS), and the main organs were toxicologically tested. The Ki-67 and PCNA positivity and the cytoplasmic marker (CD34, CD31, COX4, Cytochrome C, GLUT1, iNOS) immunoexpression in the tumor samples were quantified. The combination of nitroglycerin and metformin significantly inhibited fibrosarcoma growth in hamsters without toxicity, compared to monotherapy or control. The results were validated and confirmed in the subsequently accomplished experiment with doubled doses of the single drug therapy and in the rescue experiment with addition of mebendazole. The single treatments did not show significant antisarcoma effect, regardless of the dose. Co-treatment with mebendazole inhibited anticancer activity of the nitroglycerin and metformin combination. Mebendazole rescued tumor progression suppressed by the combination of nitroglycerin and metformin. Administration of nitroglycerin with metformin might be an effective and safe approach in novel nontoxic adjuvant and relapse prevention anticancer treatment.