Abstract
Poor prognoses remain the most challenging aspect of hepatocellular carcinoma (HCC) therapy. Consequently, alternative therapeutics are essential to control HCC. This study investigated the anticancer effects of safranal against HCC using in vitro, in silico, and network analyses. Cell cycle and immunoblot analyses of key regulators of cell cycle, DNA damage repair and apoptosis demonstrated unique safranal-mediated cell cycle arrest at G2/M phase at 6 and 12 h, and at S-phase at 24 h, and a pronounced effect on DNA damage machinery. Safranal also showed pro-apoptotic effect through activation of both intrinsic and extrinsic initiator caspases; indicating ER stress-mediated apoptosis. Gene set enrichment analysis provided consistent findings where UPR is among the top terms of up-regulated genes in response to safranal treatment. Thus, proteins involved in ER stress were regulated through safranal treatment to induce UPR in HepG2 cells.
Highlights
Despite all efforts, more people are diagnosed with hepatocellular carcinoma (HCC); the most common type of primary liver cancer and the second leading cause of cancer-related death worldwide[1]
Apoptosis was induced upon safranal treatment, which was evident from Flourescence Activated Cell Sorting (FACS) analysis data and activation of both initiator and executioner caspases
To assess the cytotoxic effects of safranal (Fig. 1a) on liver cancer in vitro, HepG2 cells were treated with a range of concentrations (50–900 μM) of safranal for 24, 48, 72 h
Summary
More people are diagnosed with hepatocellular carcinoma (HCC); the most common type of primary liver cancer and the second leading cause of cancer-related death worldwide[1]. Natural products have long been a part of folk medicine and have been playing an instrumental role in the development of anti-cancer drugs[5]. Thanks to their nontoxicity and low-to-non associated side effects, 40% of FDA-approved therapeutic agents are natural-based components or their derivatives[6]. Considering their great efficacy and low toxicity, natural products have been extensively studied and introduced as a chemopreventive therapy for many diseases including cancer[7]. The present results provided evidence that the reported safranal-induced apoptosis was mediated through endoplasmic reticulum (ER)-stress
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