A dual-target pectin-like polysaccharide LRP01B from Lamiophlomis rotata induces pancreatic cancer cell apoptosis in vitro and in vivo by causing mitochondrial dysfunction.

Pancreatic ductal adenocarcinoma (PDAC) is a highly malignant cancer with limited treatment options. Recent pharmacological studies suggested that Lamiophlomis rotata might contain components with antitumor activities. In this study, we aimed to investigate the potential of polysaccharides as active components in Lamiophlomis rotata. Our findings suggest that a polysaccharide, LRP01B, from Lamiophlomis rotata induces PDAC cells apoptosis by causing mitochondrial dysfunction and oxidative stress in vitro and in vivo. LRP01B is a homogeneous polysaccharide with a molecular weight of 15.9 kDa, composed of galactose, glucose, xylose, arabinose, rhamnose, and galacturonic acid in a molar ratio of 0.7: 0.3: 0.1: 1.1: 1.0: 4.3. The backbone of LRP01B mainly consists of 1,4-linked α-GalpA, 1,2-linked α-Rhap, and 1,3-linked α-GalpA, with existence of arabinose and xylose on the side chain. In vivo experiments demonstrate that LRP01B significantly inhibits pancreatic tumor growth in a patient-derived xenograft nude mouse model. Mechanism studies uncover that LRP01B induces apoptosis of PDAC cells through mitochondrial dysfunction and oxidative stress by recruiting TNF-related apoptosis-inducing ligand (TRAIL) to TRAIL-R1, which leads to the binding of LRP01B to both TRAIL and TRAIL-R1. Our results demonstrate that LRP01B is a dual-targeting polysaccharide with anti-PDAC activity and may be a promising anti-PDAC drug candidate.