Galactomannan tetrasaccharide targets mannose receptor to suppress hepatocellular carcinoma growth through ROS/JNK
Shuying Li1, Han Gao2, Jielin Zhao2
1National Glycoengineering Research Center and NMPA Key Laboratory for Quality Research and Evaluation of Carbohydrate-based Medicine, Shandong University, 72 Binhai Road, Qingdao 266237, China; School of Pharmaceutical Sciences, Zhejiang Chinese Medicinal University, 260 Baichuan Road, Hangzhou 311400, China.
Abstract:
Hepatocellular carcinoma (HCC) is one of the most prevalent malignant tumors worldwide. Studies have documented the antitumor activities of various polysaccharides derived from Antrodia cinnamomea (AC); however, to date, the antitumor activity of the oligosaccharide fragment related to galactomannan polysaccharide in AC remains unreported. In this study, we disclosed that the backbone tetrasaccharide derivative of AC galactomannan, designated as ACP-3, demonstrates specific binding to mannose receptors (MR) on the surface of Hep G2 cells, facilitating its cellular internalization. This interaction thereby elicited potent antiproliferative effects through dual mechanisms: ROS/JNK signaling-induced apoptosis and ROS-mediated autophagy-induced cell death. In vivo studies further validated the tumor-targeting capability of ACP-3, as monotherapy significantly suppresses the growth of H22 solid tumors. Notably, the co-administration of ACP-3 with cyclophosphamide (CTX) could synergistically enhance antitumor activity and concurrently alleviate CTX-induced adverse effects such as weight loss, hepatorenal toxicity, and immune dysfunction. These findings collectively establish ACP-3 as a promising therapeutic candidate for the treatment of HCC.
Insights
A novel compound from Antrodia cinnamomea (AC), ACP-3, targets liver cancer cells (Hepatocellular carcinoma) by inducing cell death. It also enhances chemotherapy efficacy and reduces side effects.
Area of Science:
- Biochemistry
- Pharmacology
- Oncology
Background:
- Hepatocellular carcinoma (HCC) is a major global health concern.
- Antrodia cinnamomea (AC) polysaccharides show antitumor potential, but specific oligosaccharide fragments are unexplored.
- The galactomannan fragment from AC, ACP-3, is investigated for its therapeutic effects.
Purpose of the Study:
- To investigate the antitumor activity of the AC galactomannan oligosaccharide fragment, ACP-3.
- To elucidate the mechanisms of ACP-3's antiproliferative effects on HCC cells.
- To evaluate ACP-3's efficacy and safety in vivo, alone and in combination with chemotherapy.
Main Methods:
- ACP-3 was synthesized and characterized.
- In vitro studies assessed ACP-3 binding to mannose receptors (MR) on Hep G2 cells and its antiproliferative effects via apoptosis and autophagy.
- In vivo studies evaluated ACP-3's tumor-targeting capability and its effects on H22 solid tumors, both as monotherapy and combined with cyclophosphamide (CTX).
Main Results:
- ACP-3 specifically binds to MR on Hep G2 cells, leading to internalization.
- ACP-3 induced potent antiproliferative effects through ROS/JNK signaling-induced apoptosis and ROS-mediated autophagy.
- In vivo, ACP-3 monotherapy suppressed H22 tumor growth and synergistically enhanced antitumor activity with CTX, while mitigating CTX-induced toxicity.
Conclusions:
- ACP-3 demonstrates significant antitumor activity against hepatocellular carcinoma.
- The compound exerts its effects via MR-mediated internalization and induction of apoptosis and autophagy.
- ACP-3 is a promising therapeutic candidate for HCC, with potential to improve chemotherapy outcomes.
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