Abstract
Herein, we evaluated the anti-cancer effect and molecular mechanisms of a novel betulinic acid (BA) derivative, SYK023, by using two mouse models of lung cancer driven by KrasG12D or EGFRL858R. We found that SYK023 inhibits lung tumor proliferation, without side effects in vivo or cytotoxicity in primary lung cells in vitro. SYK023 triggered endoplasmic reticulum (ER) stress. Blockage of ER stress in SYK023-treated cells inhibited SYK023-induced apoptosis. In addition, we found that the expression of cell cycle-related genes, including cyclin A2, B1, D3, CDC25a, and CDC25b decreased but, while those of p15INK4b, p16INK4a, and p21CIP1 increased following SYK023 treatment. Finally, low doses of SYK023 significantly decreased lung cancer metastasis in vitro and in vivo. Expression of several genes related to cell migration, including synaptopodin, were downregulated by SYK023, thereby impairing F-actin polymerization and metastasis. Therefore, SYK023 may be a potentially therapeutic treatment for metastatic lung cancer.
Highlights
Betulinic acid (BA), a natural pentacyclic triterpene, has a variety of beneficial biological activities, including anti-tumor, anti-viral, anti-bacterial, anti-malarial and anti-inflammatory activity [1, 2]
We found that SYK019 and SYK023 (Figure 1A1C) inhibited tumorigenesis better than BA
We recently used xenograft mouse models and a KrasG12D-induced lung cancer mouse model to assess the effect of BA, and found that it suppresses tumorigenesis by inhibiting cell cycle progression [4]
Summary
Betulinic acid (BA), a natural pentacyclic triterpene, has a variety of beneficial biological activities, including anti-tumor, anti-viral, anti-bacterial, anti-malarial and anti-inflammatory activity [1, 2]. Our previous study indicated that 20 mg/ kg of BA can inhibit lung tumor growth in the KrasG12Dinduce lung cancer mice. This dose is higher than other clinical or pre-clinical used drug. Our preliminary results show that highly frequency of lethality occurred after BA injection, suggesting that BA cause high cytotoxicity toward normal cell leadings side-effect. Based on these studies, to screen the BA derivative(s) with higher anti-tumor activity and low sideeffect is crucial for lung cancer therapy. We tried to develop a new derivative of BA to enhance its’ tumor-suppressive effect without increasing the side effect in vitro and in vivo
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