Therefore, a neoplasm can be defined as a pathological condition resulting from the interaction between tumor and microenvironment in which the latter affects the neoplastic cells growth and their ability to metastasize. In fact, it is well known that the cancer is a biological multicellular entity consisting of a heterogeneous population of tumor cells, multiple variety of cell types and normal infiltrating lymphocytes and their communication is bidirectional and dynamic. Combined therapy with multiple drugs or modalities is a common practice in the cancer treatment, which can achieve better therapeutic effects than a single drug or modality and can reduce the side effects and resistance to drugs. Other chemotherapeutics, such as epirubicin, cisplatin, 5-fluorouracil, and etoposide and their combinations, demonstrate even lower efficacy. Doxorubicin (adriamycin, DOX), antineoplastic chemotherapy drug that is a standard component in treating advanced HCC for its antitumor action, has shown insufficient efficacy, with a response rate of about 15–20%. Chemotherapy is one of the common strategies in HCC treatment, especially for unresectable tumors. Therefore, new effective and well-tolerated therapy strategies are urgently needed. However, this cancer is often diagnosed at an advanced stage when most potentially curative therapies such as resection, transplantation or percutaneous, and transarterial interventions are of limited efficacy and no response is obtained to common therapies. Although the clinical diagnosis and management of early-stage HCC have improved significantly, its prognosis is still extremely poor. The distribution of these risk factors among patients with HCC is highly variable, depending on geographic region and race or ethnic group. Less common causes include hereditary hemochromatosis, alpha1-antitrypsin deficiency, autoimmune hepatitis, some porphyrias, and Wilson’s disease. The main risk factors for HCC are hepatitis B (HBV) or C virus (HCV) infection, alcohol-induced liver disease (ALD), nonalcoholic fatty liver disease (NAFLD), primary biliary cirrhosis, exposure to environmental carcinogens (particularly aflatoxin), and then type 2 diabetes and obesity. HCC generally develops from chronic liver injury, which leads to inflammation, hepatocyte regeneration, liver matrix remodeling, fibrosis, and, finally, cirrhosis. Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide, and more than half a million new cases occur annually. In conclusion, future studies could relate to the doxorubicin/tacrolimus combination effects in mice models bearing HCC in order to see if this formulation could be useful in HCC treatment. Moreover, our results showed that the mechanisms involved were (i) a strong cell apoptosis induction, (ii) contemporaneous decrease of autophagy activation, understood as prosurvival process, and (iii) downregulation of proinflammatory cytokines. Interestingly the formulation with doxorubicin and tacrolimus induced higher cytotoxicity level on tumor cells than single treatment. Cytokines concentration in cellular supernatants after treatments was studied by Bio-Plex assay. Apoptosis-related protein PARP-1 cleaved and autophagy-related protein expressions (Beclin-1 and LC3B) were measured by western blotting analysis. Cell apoptosis was evaluated using Annexin V and Dead Cell assay.
#Calcusyn online software#
Cell viability was analyzed by Sulforhodamine B assay and synergic effect was evaluated by the software CalcuSyn. Thus, the aim of this study was to investigate whether tacrolimus (FK506) has synergistic antitumor effects with doxorubicin on two human hepatocellular carcinoma cell lines, Huh7 and HepG2. Hepatocellular carcinoma is the fifth most common cancer worldwide and shows a complex clinical course, poor response to pharmacological treatment, and a severe prognosis.