Investigating Anti-leukemic Role of Copper Dithiocarbamate Using Wnt and HIF 1 Alpha Pathway Markers in AML Rat Model

Abstract

Acute leukemia’s are typically life-threatening affliction in which cancerous alteration occurs in the early progenitors or haemopoietic stem cell with a high mortality rate. There is both inability of haemopoietic stem cell to differentiate and excessive proliferation in stem cell compartment causing buildup of non-functional cells known as myeloblasts. The clinical and biological discrepancy towards therapy resistance in this haematological disorder makes treatment complex that highlight the need to explore and develop novel therapeutic compounds that must show better efficacy and low toxicity then currently available conventional chemotherapeutic drugs. In present study, anti-leukemic potential of a novel dithiocarbamate derivative named copper dithiocarbamate (CuDTC) was investigated as an individual drug and in combination with known chemotherapy (Doxorubicin) in benzene-induced leukemic rat model. The compound was first characterized by XRD and Scanning electron microscopy (SEM). To investigate antileukemic potential of the test compound, it was administered to benzene induced leukemic rat model. For this purpose, different parameters were analyzed including haematological, morphological, biochemical (LFTs, RFTs, lipid profile and LDH) and relative mRNA expression of the well-known proliferative biomarkers of Wnt and HIF-1α pathway: AXIN, GSK3β, LEF, HIF-1α, HSP90 and PTEN in samples obtained from different experimental groups. It was revealed that, in isolation CuDTC showed remarkable recovery of cellular indicators comparative to leukemic conditions. Blood cell counts, hepatic and renal biomarkers of compound treated leukemic rats were significantly improved. The relative expression of AXIN, GSK3β, LEF, HIF-1α, HSP90 and PTEN was also recovered significantly to normal in the CuDTC treated group comparative to benzene induced leukemic rats. However, it was observed that expression of aberrant proliferative genetic markers in combination therapy did not show significant improvements. Therefore, we conclude that CuDTC as individual therapeutic drug may serve as an exceptional therapeutic agent to treat benzene induced leukemia at haematological, biochemical, morphological as well as relative expression level against AML, whereas, further research is needed to assess the efficacy of the co-administration of CuDTC and traditional therapy against leukemia