Isolinderalactone sensitizes oxaliplatin-resistance colorectal cancer cells through JNK/p38 MAPK signaling pathways
- Phytomedicine. 2022 Oct:105:154383. doi: 10.1016/j.phymed.2022.154383.
- 1. Department of Pharmacy, College of Pharmacy, Mokpo National University, Muan 58554, Republic of Korea.
- 2. Department of Pharmacy, College of Pharmacy, Mokpo National University, Muan 58554, Republic of Korea; Department of Biomedicine, Health & Life Convergence Sciences, BK21 Four, College of Pharmacy, Mokpo National University, Jeonnam 58554, Republic of Korea.
- 3. Department of Biomedicine, Health & Life Convergence Sciences, BK21 Four, College of Pharmacy, Mokpo National University, Jeonnam 58554, Republic of Korea.
- 4. Department of Biological Sciences, Keimyung University, Daegu, 42601, Republic of Korea.
- 5. Department of Dental Pharmacology, School of Dentistry, Jeonbuk National University, Jeonju 54896, Republic of Korea.
- 6. College of Korean Medicine, Dongshin University, Naju, Jeollanam 58245, Republic of Korea.
- 7. College of Pharmacy, Daegu Catholic University, Gyeongbuk 38430, Korea.
- 8. Department of Pharmacy, College of Pharmacy, Mokpo National University, Muan 58554, Republic of Korea; Department of Biomedicine, Health & Life Convergence Sciences, BK21 Four, College of Pharmacy, Mokpo National University, Jeonnam 58554, Republic of Korea; The China-US (Henan) Hormel Cancer Institute, Zhengzhou, Henan, 450008, PR China. Electronic address: [email protected].
Background: Isolinderalactone (ILL), a sesquiterpene lactone compound, can be extracted from the root of Lindera aggregate. Physiological activities of ILL, including anti-inflammatory and anti-proliferative effects, have been investigated in multiple diseases. Nevertheless, little is known regarding its anti-cancer activities and the mechanism of action of ILL in targeting human CRC cells.
Purpose: To determine ILL-mediated anti-proliferative effects on oxaliplatin (Ox)-sensitive and resistant colorectal Cancer (CRC) cells and underlying mechanisms involved in its effects focusing on signal transduction.
Methods: Inhibitory effect of ILL on CRC cells was evaluated by analyzing mitochondrial membrane potential (MMP) dysfunction and multi-caspase activity. Apoptosis-regulating proteins and JNK/p38 signaling molecules were monitored by Western blotting. ROS-dependent physiological modifications by ILL were confirmed by pretreatment with N-acetylcysteine (NAC). Moreover, the involvement of JNK/p38 signaling in ROS-mediated Apoptosis was verified by treatment with SP600125 (JNK Inhibitor) and SB203580 (p38 inhibitor).
Results: ILL decreased cell viability and colony formation in both CRC Ox-sensitive (HCT116 and HT29) and Ox-resistant (OxR) (HCT116-OxR and HT29-OxR) cells. ILL induced G2/M phase cell cycle arrest, ROS generation, phosphorylated (p)JNK/p38 MAPK activation, mitochondrial membrane potential (MMP) depolarization, and multi-caspase activation, which eventually triggered apoptotic cell death of CRC cells. In addition, combined treatment with ILL and SP600125, SB203580, or pan-caspase inhibitor (Z-VAD-FMK) prevented decreases in cell viability seen after treatment with ILL alone. Pretreatment with NAC attenuated ILL-mediated Apoptosis, ROS production, and p-JNK/p38 expression.
Conclusion: Taken together, our results suggest that ILL can exert its Anticancer effect in CRC Ox-sensitive and OxR cells by inducing ROS-mediated Apoptosis through JNK/p38 MAPK signaling pathways. This is the first study demonstrating that ILL has a potential to improve drug efficacy against resistance mechanisms, providing a new insight into therapeutic strategies targeting drug-resistant CRC.
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