Heteronemin and tetrac derivatives suppress non-small cell lung cancer growth via ERK1/2 inhibition

Cheng-Chin Chung; Tung-Yung Huang; Hung-Ru Chu; Roberto De Luca; Elena Candelotti; Chi-Hung Huang; Yu-Chen S H Yang; Sandra Incerpi; Jens Z Pedersen; Chi-Yu Lin; Haw-Ming Huang; Sheng-Yang Lee; Zi-Lin Li; Chun A ChangOu; Wen-Shan Li; Paul J Davis; Hung-Yun Lin; Jacqueline Whang-Peng; Kuan Wang

doi:10.1016/j.fct.2022.112850

Heteronemin and tetrac derivatives suppress non-small cell lung cancer growth via ERK1/2 inhibition

Food Chem Toxicol. 2022 Mar:161:112850. doi: 10.1016/j.fct.2022.112850. Epub 2022 Feb 10.

Authors

Cheng-Chin Chung¹, Tung-Yung Huang², Hung-Ru Chu³, Roberto De Luca⁴, Elena Candelotti⁵, Chi-Hung Huang⁶, Yu-Chen S H Yang⁷, Sandra Incerpi⁸, Jens Z Pedersen⁹, Chi-Yu Lin¹⁰, Haw-Ming Huang¹¹, Sheng-Yang Lee¹², Zi-Lin Li¹³, Chun A ChangOu¹⁴, Wen-Shan Li¹⁵, Paul J Davis¹⁶, Hung-Yun Lin¹⁷, Jacqueline Whang-Peng¹⁸, Kuan Wang¹⁹

Affiliations

¹ Graduate Institute of Cancer Molecular Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University and Academia Sinica, Taipei, Taiwan; Taipei Medical University Hospital, Taipei Medical University, Taipei, Taiwan. Electronic address: james092778@gmail.com.
² Graduate Institute of Cancer Molecular Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan; Graduate Institute of Nanomedicine and Medical Engineering, College of Medical Engineering, Taipei Medical University, Taipei, Taiwan. Electronic address: charvel0203@gmail.com.
³ Graduate Institute of Cancer Molecular Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan; Graduate Institute of Nanomedicine and Medical Engineering, College of Medical Engineering, Taipei Medical University, Taipei, Taiwan. Electronic address: a0918362166@tmu.edu.tw.
⁴ Department of Sciences, University Roma Tre, Rome, Italy. Electronic address: rdeluca@bidmc.harvard.edu.
⁵ Department of Sciences, University Roma Tre, Rome, Italy. Electronic address: elena.candelotti@uniroma3.it.
⁶ Division of Cardiology, Department of Internal Medicine, Cathay General Hospital, Taipei, Taiwan. Electronic address: hchbox@cgh.org.tw.
⁷ Joint Biobank, Office of Human Research, Taipei Medical University, Taipei, Taiwan. Electronic address: can_0131@tmu.edu.tw.
⁸ Department of Sciences, University Roma Tre, Rome, Italy. Electronic address: sandra.incerpi@uniroma3.it.
⁹ Department of Biology, University of Rome Tor Vergata, Rome, Italy. Electronic address: j.z.pedersen@gmail.com.
¹⁰ School of Dentistry, College of Oral Medicine, Taipei Medical University, Taipei, Taiwan. Electronic address: alexlin1018@gmail.com.
¹¹ School of Dentistry, College of Oral Medicine, Taipei Medical University, Taipei, Taiwan. Electronic address: hhm@tmu.edu.tw.
¹² School of Dentistry, College of Oral Medicine, Taipei Medical University, Taipei, Taiwan; Dentistry, Wan-Fang Medical Center, Taipei Medical University, Taipei 11031, Taiwan. Electronic address: seanlee@tmu.edu.tw.
¹³ Graduate Institute of Cancer Molecular Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan; Graduate Institute of Nanomedicine and Medical Engineering, College of Medical Engineering, Taipei Medical University, Taipei, Taiwan. Electronic address: lizilin0919@gmail.com.
¹⁴ Core Facility Center, Office of Research and Development, Taipei Medical University, Taipei, Taiwan; Integrated Laboratory, Center of Translational Medicine, Taipei Medical University, Taipei, Taiwan. Electronic address: austinc99@tmu.edu.tw.
¹⁵ Laboratory of Chemical Biology and Medicinal Chemistry, Institute of Chemistry, Academia Sinica, Taipei, Taiwan. Electronic address: wenshan@gate.sinica.edu.tw.
¹⁶ Pharmaceutical Research Institute, Albany College of Pharmacy and Health Sciences, Albany, NY, USA. Electronic address: pdavis.ordwayst@gmail.com.
¹⁷ Graduate Institute of Cancer Molecular Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan; Doctoral Degree Program in Marine Biotechnology, National Sun Yat-Sen University, Kaohsiung, Taiwan; Department of Medicine, Albany Medical College, Albany, NY, USA; TMU Research Center of Cancer Translational Medicine, Taipei Medical University, Taipei, Taiwan; Traditional Herbal Medicine Research Center of Taipei Medical University Hospital, Taipei Medical University, Taipei, Taiwan. Electronic address: linhy@tmu.edu.tw.
¹⁸ Graduate Institute of Cancer Molecular Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan; Cancer Center, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan. Electronic address: jqwpeng@nhri.org.tw.
¹⁹ Graduate Institute of Nanomedicine and Medical Engineering, College of Medical Engineering, Taipei Medical University, Taipei, Taiwan. Electronic address: wangk007@gmail.com.

PMID: 35151786
DOI: 10.1016/j.fct.2022.112850

Abstract

The most common cancer, lung cancer, causes deaths worldwide. Most lung cancer patients have non-small cell lung carcinomas (NSCLCs) with a poor prognosis. The chemotherapies frequently cause resistance therefore search for new effective drugs for NSCLC patients is an urgent and essential issue. Deaminated thyroxine, tetraiodothyroacetic acid (tetrac), and its nano-analogue (NDAT) exhibit antiproliferative properties in several types of cancers. On the other hand, the most abundant secondary metabolite in the sponge Hippospongia sp., heteronemin, shows effective cytotoxic activity against different types of cancer cells. In the current study, we investigated the anticancer effects of heteronemin against two NSCLC cell lines, A549 and H1299 cells in vitro. Combined treatment with heteronemin and tetrac derivatives synergistically inhibited cancer cell growth and significantly modulated the ERK1/2 and STAT3 pathways in A549 cells but only ERK1/2 in H1299 cells. The combination treatments induce apoptosis via the caspases pathway in A549 cells but promote cell cycle arrest via CCND1 and PCNA inhibition in H1299 cells. In summary, these results suggest that combined treatment with heteronemin and tetrac derivatives could suppress signal transduction pathways essential for NSCLC cell growth. The synergetic effects can be used potentially as a therapeutic procedure for NSCLC patients.

Keywords: Cell growth; ERK1/2; Heteronemin; NDAT; Non-small cell lung cancer; STAT3; Tetrac.

MeSH terms

Antineoplastic Agents / pharmacology
Carcinoma, Non-Small-Cell Lung / drug therapy*
Cell Line, Tumor
Drug Therapy, Combination
Extracellular Signal-Regulated MAP Kinases / genetics
Extracellular Signal-Regulated MAP Kinases / metabolism*
Gene Expression Regulation, Neoplastic / drug effects
Humans
Lung Neoplasms / drug therapy*
Terpenes / pharmacology*
Thyroxine / analogs & derivatives*
Thyroxine / pharmacology

Substances

Antineoplastic Agents
Terpenes
heteronemin
Extracellular Signal-Regulated MAP Kinases
tetraiodothyroacetic acid
Thyroxine