Diarylheptanoids/sorafenib as a potential anticancer combination against hepatocellular carcinoma: the p53/MMP9 axis of action

• Published in: Naunyn-Schmiedeberg's archives of pharmacology Vol. 396; no. 10; pp. 2501 - 2517
• Main Authors: Elmetwalli, Alaa, Diab, Thoria, Albalawi, Aisha Nawaf, El-Naggar, Sabry Ali, El‑Far, Ali H., Ghedan, Amira Radwan, Alamri, Eman Saad, Salama, Afrah Fatthi
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01-10-2023; Springer Nature B.V
• Subjects: Angiogenesis; Animals; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; Antineoplastic drugs; Antitumor activity; Antitumor agents; Apoptosis; Biomedical and Life Sciences; Biomedicine; Carcinoma, Hepatocellular - pathology; Cell Line, Tumor; Cytotoxicity; Enzymes; Gelatinase B; Hepatocellular carcinoma; Inflammation; Interleukin 6; Interleukin-6 - metabolism; Liver cancer; Liver Neoplasms - pathology; Matrix metalloproteinase; Matrix Metalloproteinase 9 - genetics; Matrix Metalloproteinase 9 - metabolism; Mice; Molecular Docking Simulation; Neurosciences; p53 Protein; Pharmacology/Toxicology; Sorafenib - pharmacology; Tumor Suppressor Protein p53 - genetics; Tumors; Vascular endothelial growth factor; Vascular Endothelial Growth Factor A - metabolism; HCC; Diarylheptanoid; Antioxidant; Cancer-targeting
• ISSN: 0028-1298; 1432-1912; 1432-1912
• DOI: 10.1007/s00210-023-02470-0

Hepatocellular carcinoma (HCC) is a serious and potentially fatal form of cancer associated with liver damage. New anticancer drugs are increasingly needed due to the increasing number of cancer cases every year. In this study, diarylheptanoids (DAH) from
Alpinia officinarum
were examined for their antitumor activity against DAB-induced HCC in mice, as well as their ability to reduce liver damage. Assays for cytotoxicity were conducted using MTT. The DAB-induced HCC Swiss albino male mice were given DAH and sorafenib (SOR) either as single treatments or in combination, and the effects on tumour development and progression were monitored. Malondialdehyde (MDA) and total superoxide dismutase (T-SOD) were evaluated along with biomarkers of liver enzymes (AST, ALT, and GGT). The apoptosis-related gene (
CASP8
), the apoptosis-related gene (
p53
), the anti-inflammatory genes (
IL-6
), the migration-related gene matrix metalloprotease-9 (
MMP9
), and the angiogenesis-related gene vascular endothelial growth factor (
VEGF
) were assessed using qRT-PCR in the hepatic tissue. As a final step, DAH and SOR were docked with
CASP8
and
MMP9
via molecular docking to propose potential mechanisms of action. Our results revealed that the combination of DAH and SOR has a potent inhibitory effect on the growth and viability of the HepG2 cell line. The outcomes demonstrated that DAH and SOR-treated HCC-bearing mice displayed a reduction in the tumour burden and liver damage as demonstrated by (1) parameters of repaired liver function; (2) low levels of hepatic MDA; (3) elevated levels of hepatic T-SOD; (4)
p53
,
IL-6
,
CASP8
,
MMP9
, and
VEGF
downregulation; and (5) enhanced hepatic structure. The best results were revealed in mice that were co-treated with DAH (given orally) and SOR (given intraperitoneally). The docking study also proposed that both DAH and SOR could inhibit
CASP8
and
MMP9
’s oncogenic activities and had a high affinity for these enzymes. In conclusion, according to study findings, DAH enhances SOR antiproliferative and cytotoxic effects and identifies their molecular targets. Furthermore, the results revealed that DAH was able to boost the anticancer effects of the drug SOR and reduce liver damage caused by HCC in mice. This suggests that DAH could be a potential therapeutic agent against liver cancer.