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

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

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: pelobie@sz.tsinghua.edu.cn.
  • 11 Laboratory of Chemical Biology, Department of Studies in Organic Chemistry, University of Mysore, Manasagangotri, Mysuru-570006, India. Electronic address: basappa@chemistry.uni-mysore.ac.in.
  • 12 Department of Science in Korean Medicine, Kyung Hee University, 24 Kyungheedae-ro, Dongdaemun-gu, Seoul 02447, Republic of Korea. Electronic address: ksahn@khu.ac.kr.
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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