Abstract
Twenty-one xanthone derivatives (XDs) were synthesized by a microwave-assisted technique. Their in vitro inhibition potency against the growth of four cancer cell lines was evaluated. XD-1 ∼ [6,9,10-trihydroxy-3,3-dimethyl-5-(2-methylbut-3-en-2-yl)-3H,7H-pyrano[2,3-c]xanthen-7-one] was confirmed as the most active agent against HepG2 cell line growth with IC50 of 18.6 ± 2.31 μM. Apoptosis analysis indicated different contributions of early/late apoptosis and necrosis to cell death for XD-1. XD-1 arrested HepG2 cells on the G0/G1 phase, as indicated by the decreased expressions of cyclin D and CDK2 and the increased expressions of p21. Western blot implied that XD-1 regulated p53/MDM2 to a better healthier state. Moreover, XD-1-induced cell apoptosis was mitochondrion-mediated, as evidenced by caspase activation and involved the PI3K/AKT/mTOR signaling pathway. All the evidence supports that XD-1 is a significant anti-cancer agent for HCC.
Highlights
Primary hepatic cancer is one of the common causes of cancerrelated death.[1]
Given the pivotal role of the PI3K/AKT/mTOR pathway in controlling cell apoptosis, we explored whether xanthone derivatives (XDs)-1 inhibits the PI3K/AKT/mTOR pathway
3.6 XD-1 regulates the p53/MDM2 status and inhibits PI3K/ AKT/mTOR in HepG2 cells p53 is a tumor suppressor that plays a pivotal role in inducing cell cycle arrest, DNA repair, senescence, and apoptosis
Summary
Primary hepatic cancer is one of the common causes of cancerrelated death.[1]. About 75–85% of patients with primary liver cancer have hepatocellular carcinoma (HCC).[2]. Surgical resection, orthotopic liver transplantation, and local ablative therapies are considered potentially curative for early-stage HCC patients.[3] Sorafenib is the only chemotherapy drug approved by the US Food and Drug Administration for rst-line treatment of advanced HCC and remains the only drug approved for the systemic treatment of patients with metastatic HCC.[4] despite advances in tumor treatments, no effective systemic therapy has been established for advanced HCC. The 5 year survival rate for liver cancer a er receiving systemic treatment is still poor,[5] and severe side effects limit the clinical applications of the chemotherapy agents in advanced HCC treatment.[6] In summary, novel, effective therapeutic agents with low toxicity are urgently needed
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