Abstract
Cardamonin (CADMN) exerts an in vitro antiproliferative and apoptotic actions against human hepatocellular carcinoma cells (HepG2). This study aimed to investigate the in vivo anti-tumorigenic action of CADMN against human hepatocellular carcinoma xenografts in an athymic nude mice, as well as to study the molecular docking and safety profile of this compound. Acute toxicity study demonstrated that CADMN is safe and well-tolerated up to 2000 mg/kg in ICR mice. Oral administration of 50 mg/kg/day of CADMN in xenografted nude mice showed a significant suppression in tumor growth as compared to untreated control group without pronounced toxic signs. Immunohistochemistry assay showed downregulation of proliferative proteins such as PCNA and Ki-67 in treated groups as compared to untreated control. Additionally, immunofluorescence analysis showed a significant downregulation in anti-apoptotic Bcl-2 protein, whereas pre-apoptotic Bax protein was significantly upregulated in nude mice treated with 25 and 50 mg/kg CADMN as compared to untreated mice. The findings also exhibited down-regulation of NF-κB-p65, and Ikkβ proteins, indicating that CADMN deactivated NF-κB pathway. The molecular docking studies demonstrated that CADMN exhibits good docking performance and binding affinities with various apoptosis and proliferation targets in hepatocellular cancer cells. In conclusion, CADMN could be a potential anticancer candidate against hepatocellular carcinoma. Other pharmacokinetics and pharmacodynamics properties, however, need to be further investigated in depth.
Highlights
The geographical mapping of hepatocellular carcinoma (HCC) indicates that the incidence and mortality rate of HCC has changed over time, HCC is still the fourth most commonBiomedicines 2020, 8, 586; doi:10.3390/biomedicines8120586 www.mdpi.com/journal/biomedicinesBiomedicines 2020, 8, 586 cause of cancer deaths worldwide [1]
C, caspase 7, caspase 8, caspase 9, proliferating cell nuclear antigen (PCNA), NF-κB, and NF-κB-p65 with active conformation of each ligand consists of CADMN and 5-FU clearly revealed that numerous potential interactions were present (Supplemental Materials Figures S2–S11)
The findings of our study indicated that CADMN has anti-tumorigenic effect on HepG2 cells as a result of apoptosis and inhibition of NF-κB pathway via down regulation of anti-apoptotic Bcl-2 protein, p-NF-κB-p65, and Ikkβ proteins, while pre-apoptotic Bax protein was significantly over-expressed
Summary
The geographical mapping of hepatocellular carcinoma (HCC) indicates that the incidence and mortality rate of HCC has changed over time, HCC is still the fourth most commonBiomedicines 2020, 8, 586; doi:10.3390/biomedicines8120586 www.mdpi.com/journal/biomedicinesBiomedicines 2020, 8, 586 cause of cancer deaths worldwide [1]. Several problems have arisen in the treatment of HCC, including drug resistance and high recurrence rate [3]. The absence of curative treatment for HCC encouraged scientists to conduct an intensive pharmacological studies to find alternative anticancer agents with better safety and effectiveness profile to treat HCC [4,5]. The cytotoxic activities of CADMN have been reported against several cancer cell lines including U266 (myeloma), A549 (lung), MDA-MB-231 (breast), DU145 (prostate), MCF-7 (breast), and SGC7901 (gastric) [7,8,9,10,11]. In our earlier published in vitro study, CADMN has been reported to exert anti-proliferative and apoptotic action in hepatocellular carcinoma cells (HepG2) through enhancing the ROS accumulation, which lead to an inhibition of NF-κB translocation [15].
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