Oxazine drug-seed induces paraptosis and apoptosis through reactive oxygen species/JNK pathway in human breast cancer cells

  • Transl Oncol. 2024 Nov:49:102101. doi: 10.1016/j.tranon.2024.102101.
Na Young Kim  1 ,  Dukanya Dukanya  2 ,  Gautam Sethi  3 ,  Swamy S Girimanchanaika  2 ,  Jirui Yang  4 ,  Omantheswara Nagaraja  5 ,  Ananda Swamynayaka  5 ,  Divakar Vishwanath  2 ,  Keerthikumara Venkantesha  5 ,  Shreeja Basappa  6 ,  Arunachalam Chinnathambi  7 ,  Sulaiman Ali Alharbi  7 ,  Mahendra Madegowda  5 ,  Alexey Sukhorukov  8 ,  Vijay Pandey  9 ,  Peter E Lobie  10 ,  Basappa Basappa  11 ,  Kwang Seok Ahn  12
Affiliations
  • 1. Department of Science in Korean Medicine, Kyung Hee University, 24 Kyungheedae-ro, Dongdaemun-gu, Seoul 02447, Republic of Korea.
  • 2. Laboratory of Chemical Biology, Department of Studies in Organic Chemistry, University of Mysore, Manasagangotri, Mysuru-570006, India.
  • 3. Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, 16 Medical Drive, 117600, Singapore.
  • 4. Tsinghua Berkeley Shenzhen Institute, Tsinghua Shenzhen International Graduate School, Tsinghua University, Shenzhen-518055, Guangdong, China.
  • 5. Department of Studies in Physics, University of Mysore, Manasagangotri, Mysuru-570006, India.
  • 6. Department of Chemistry, BITS-Pilani Hyderabad Campus, Jawahar Nagar, Medchal-500078, India.
  • 7. Department of Botany and Microbiology, College of Science, King Saud University, PO Box-2455, Riyadh 11451, Saudi Arabia.
  • 8. N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, Leninsky prospect, 47, Moscow, 119991, Russia.
  • 9. Tsinghua Berkeley Shenzhen Institute, Tsinghua Shenzhen International Graduate School, Tsinghua University, Shenzhen-518055, Guangdong, China; Institute of Biopharmaceutical and Health Engineering, Tsinghua Shenzhen, International Graduate School, Tsinghua University, Shenzhen-518055, Guangdong, China.
  • 10. Tsinghua Berkeley Shenzhen Institute, Tsinghua Shenzhen International Graduate School, Tsinghua University, Shenzhen-518055, Guangdong, China; Institute of Biopharmaceutical and Health Engineering, Tsinghua Shenzhen, International Graduate School, Tsinghua University, Shenzhen-518055, Guangdong, China; Shenzhen Bay Laboratory, Shenzhen 518055, Guangdong, China. Electronic address: [email protected].
  • 11. Laboratory of Chemical Biology, Department of Studies in Organic Chemistry, University of Mysore, Manasagangotri, Mysuru-570006, India. Electronic address: [email protected].
  • 12. Department of Science in Korean Medicine, Kyung Hee University, 24 Kyungheedae-ro, Dongdaemun-gu, Seoul 02447, Republic of Korea. Electronic address: [email protected].
PMID: 39159553 DOI: 10.1016/j.tranon.2024.102101
Abstract

Small molecule-driven JNK activation has been found to induce Apoptosis and Paraptosis in Cancer cells. Herein pharmacological effects of synthetic oxazine (4aS, 7aS)-3-((4-(4‑chloro-2-fluorophenyl)piperazin-1-yl)methyl)-4-phenyl-4, 4a, 5, 6, 7, 7a-hexahydrocyclopenta[e] [1,2]oxazine (FPPO; BSO-07) on JNK-driven Apoptosis and Paraptosis has been demonstrated in human breast Cancer (BC) MDA-MB231 and MCF-7 cells respectively. BSO-07 imparted significant cytotoxicity in BC cells, induced activation of JNK, and increased intracellular Reactive Oxygen Species (ROS) levels. It also enhanced the expression of apoptosis-associated proteins like PARP, Bax, and phosphorylated p53, while decreasing the levels of Bcl-2, Bcl-xL, and Survivin. Furthermore, the drug altered the expression of proteins linked to Paraptosis, such as ATF4 and CHOP. Treatment with N-acetyl-cysteine (antioxidant) or SP600125 (JNK Inhibitor) partly reversed the effects of BSO-07 on Apoptosis and Paraptosis. Advanced in silico bioinformatics, cheminformatics, density Fourier transform and molecular electrostatic potential analysis further demonstrated that BSO-07 induced Apoptosis and Paraptosis via the ROS/JNK pathway in human BC cells.

Keywords
Apoptosis; Breast cancer; JNK; Oxazine; Paraptosis; ROS.
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