Danshen improves survival of patients with advanced lung cancer and targeting the relationship between macrophages and lung cancer cells

// Ching-Yuan Wu 1, 2 , Jong-Yuh Cherng 3 , Yao-Hsu Yang 1, 2 , Chun-Liang Lin 4, 5 , Feng-Che Kuan 6 , Yin-Yin Lin 1 , Yu-Shih Lin 7 , Li-Hsin Shu 1 , Yu-Ching Cheng 1 , Hung Te Liu 1 , Ming-Chu Lu 6 , Jthau Lung 8 , Pau-Chung Chen 9, 17 , Hui Kuan Lin 10, 11, 12, 13 , Kuan-Der Lee 6, 16 and Ying-Huang Tsai 14, 15 1 Department of Chinese Medicine, Chiayi Chang Gung Memorial Hospital, Chiayi, Taiwan 2 School of Chinese medicine, College of Medicine, Chang Gung University, Tao-Yuan, Taiwan 3 Department of Chemistry and Biochemistry, National Chung Cheng University, Taiwan 4 Departments of Nephrology, Chiayi Chang Gung Memorial Hospital, Chiayi, Taiwan 5 Kidney and Diabetic Complications Research Team (KDCRT), Chiayi Chang Gung Memorial Hospital, Chiayi, Taiwan 6 Department of Hematology and oncology, Chiayi Chang Gung Memorial Hospital, Chiayi, Taiwan 7 Department of Pharmacy, Chiayi Chang Gung Memorial Hospital, Chiayi, Taiwan 8 Department of Medical Research and Development, Chang Gung Memorial Hospital, Chiayi branch, Taiwan 9 Institute of Occupational Medicine and Industrial Hygiene, National Taiwan University College of Public Health, Taipei, Taiwan 10 Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA 11 Department of Cancer Biology, Wake Forest University School of Medicine, Medical Center Blvd, Winston-Salem, NC, USA 12 Graduate Institute of Basic Medical Science, China Medical University, Taichung, Taiwan 13 Department of Biotechnology, Asia University, Taichung, Taiwan 14 Division of Pulmonary and Critical Care Medicine of Chang Gung Memorial Hospital, Chiayi, Taiwan, Department of Respiratory Therapy, Chang Gung University, Taoyuan, Taiwan 15 Chang-Gung University College of Medicine, Taoyuan, Taiwan 16 Division of Hematology and Oncology, Department of Internal Medicine, Taipei Medical University Hospital, Taiwan 17 Department of Environmental and Occupational Medicine, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan Correspondence to: Ying-Huang Tsai, email: chestmed@adm.cgmh.org.tw Ching-Yuan Wu, email: smbepigwu77@gmail.com Keywords: dihydroisotanshinone I, macrophage, lung cancer, Skp2, CCL2 Received: February 15, 2017      Accepted: June 10, 2017      Published: June 28, 2017 ABSTRACT In traditional Chinese medicine, Salvia miltiorrhiza Bunge (danshen) is widely used in the treatment of numerous cancers. However, its clinical effort and mechanism in the treatment of advanced lung cancer are unclear. In our study, the in vivo protective effort of danshen in patients with advanced lung cancer were validated using data from the National Health Insurance Research Database in Taiwan. We observed in vitro that dihydroisotanshinone I (DT), a bioactive compound in danshen, exerts anticancer effects through many pathways. First, 10 μM DT substantially inhibited the migration ability of lung cancer cells in both macrophage and macrophage/lung cancer direct mixed coculture media. Second, 10 μM DT repressed the phosphorylation of signal transducer and activator of transcription 3 (STAT3), the protein expression of S-phase kinase associated protein-2 (Skp2), and the mRNA levels of STAT3-related genes, including chemokine (C–C motif) ligand 2 (CCL2). In addition, 10 μM DT suppressed the macrophage recruitment ability of lung cancer cells by reducing CCL2 secretion from both macrophages and lung cancer cells. Third, 20 μM DT induced apoptosis in lung cancer cells. Furthermore, DT treatment significantly inhibited the final tumor volume in a xenograft nude mouse model. In conclusion, danshen exerts protective efforts in patients with advanced lung cancer. These effects can be attributed to DT-mediated interruption of the cross talk between lung cancer cells and macrophages and blocking of lung cancer cell proliferation.