Therapeutic Effects of Crocin Alone or in Combination with Sorafenib against Hepatocellular Carcinoma: In Vivo & In Vitro Insights

Abstract

This study investigated the therapeutic effects of the phytochemical crocin alone or in combination with sorafenib both in rats chemically induced with hepatocellular carcinoma (HCC) and in human liver cancer cell line (HepG2). Male rats were randomly divided into five groups, namely, control group, HCC induced group, and groups treated with sorafenib, crocin or both crocin and sorafenib. HCC was induced in rats with a single intraperitoneal injection of diethylnitrosamine (DEN), then 2-acetylaminofluorene (2-AAF). The HCC-induced rats showed a significant decrease in body weight compared to animals treated with either or both examined drugs. Serum inflammatory markers (C-reactive protein (CRP); interleukin-6 (IL-6); lactate dehydrogenase (LDH), and oxidative stress markers were significantly increased in the HCC group and were restored upon treatment with either or both of therapeutic molecules. Morphologically, the HCC-induced rats manifested most histopathological features of liver cancer. Treatment with either or both of crocin and sorafenib successfully restored normal liver architecture. The expression of key genes involved in carcinogenesis (TNFα, p53, VEGF and NF-κB) was highly augmented upon HCC induction and was attenuated post-treatment with either or both examined drugs. Treatment with both crocin and sorafenib improved the histopathological and inflammation parameters as compared to single treatments. The in vivo anti-cancer effects of crocin and/or sorafenib were supported by their respective cytotoxicity on HepG2 cells. Crocin and sorafenib displayed an anti-tumor synergetic effect on HepG2 cells. The present findings demonstrated that a treatment regimen with crocin and sorafenib reduced liver toxicity, impeded HCC development, and improved the liver functions.

Synthesis, docking study, and antitumor evaluation of benzamides and oxadiazole derivatives of 3‐phenoxybenzoic acid as VEGFR‐2 inhibitors

“…Although we did not evaluate the combined effects of sorafenib and Compound 4d in this work, we anticipate the combination to improve Compound 4d 's effects on proliferation inhibition and VEGFR enzyme activity. Sorafenib's synergistic effects with other compounds, such as quercetin (Abdu et al, 2022a) and crocin (Abdu et al, 2022b; Awad et al, 2023) have previously been reported.…”

Sorafenib Alleviates Inflammatory Signaling of Tumor Microenvironment in Precancerous Lung Injuries

“…In parallel to this, lung tissue TNF-α and IL-1β levels were decreased with the administration of SOR. It was previously reported that SOR reduces TNF-α and IL-16 levels in liver cancer in vitro [ 63 ]. To our knowledge, this is the first attempt to evaluate the effect of SOR on lung JNK and lung TNF-α and IL-1β levels in vivo after DEN administration.…”

Drug co-administration in the tumor immune microenvironment of Hepatocellular carcinoma

“…The regimen of crocin and sorafenib reduced hepatotoxicity, inhibited the development of HCC, and improved liver function while affecting interleukin-6 (IL-6) expression. Patients with HCC had significantly increased levels of lactate dehydrogenase (LDH) and oxidative stress markers, and crocin and sorafenib showed synergistic anti-tumor effects on HepG2 cells [25] .…”