Sensitizing effects of an organovanadium compound during adjuvant therapy with cyclophosphamide in a murine tumor model

- The sensitizing efficacy of an organovanadium compound (VC-IV) was evaluated.
- VC-IV in combination with cyclophosphamide reduced tumor burden and enhanced survivability.
- It generated ROS and induced apoptosis through p53-dependent mitochondrial pathway.
- VC-IV also protected host cells and organs from cyclophosphamide-induced toxicity.
- Thus, VC-IV enhanced the efficacy of chemotherapy-based regimens.

Various epidemiological and preclinical studies have already established the cancer chemopreventive potential of vanadium. In addition, recent studies have also indicated the abilities of vanadium-based compounds to induce cell death selectively towards malignant cells. Therefore, the objective of the present investigation is to improve the therapeutic efficacy and toxicity profile of an alkylating agent, cyclophosphamide, by the concurrent use of an organovanadium compound, oxovanadium(IV)-l-cysteine methyl ester complex (VC-IV). In this study, VC-IV (1 mg/kg b.w., p.o.) was administered alone as well as in combination with cyclophosphamide (25 mg/kg b.w., i.p.) in concomitant and pretreatment schedules. The results showed that VC-IV in combination with cyclophosphamide resulted in an improved therapeutic efficacy as evidenced by reduction of tumor growth and prolongation of life span. The observed potentiation was mediated through generation of ROS in tumor cells, which ultimately led to significant DNA damage, and apoptosis in tumor cells. Further studies revealed that VC-IV sensitized tumor cells to cyclophosphamide therapy by down-regulating the anti-apoptotic protein Bcl-2 and by up-regulating molecules like p53, Bax, cytochrome c, caspases, which led to PARP cleavage and apoptosis. Significant inhibition of angiogenesis along with reduction in the levels of VEGF-A and MMP-9 in the tumor bed by VC-IV further contributed to the sensitization accomplished by VC-IV. Moreover, VC-IV ameliorated cyclophosphamide-induced hematopoietic, hepatic and genetic damages by modulating the antioxidant status in normal organs. Thus, the present study clearly demonstrated the sensitizing and protective efficacy of VC-IV and indicates it may serve as a promising adjuvant in cancer chemotherapy.

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