br Carpizo DR D Angelica M
17. Carpizo DR, D’Angelica M. Liver resection for metastatic colorectal cancer in the presence of extrahepatic disease. Lancet Oncol. 2009;10:801e809.
18. Elias D, Ouellet JF, Bellon N, Pignon JP, Pocard M, Lasser P. Extrahepatic disease does not contraindicate hepatectomy for colorectal liver metastases. Br J Surg. 2003;90:567e574.
19. Limmer S, Oevermann E, Killaitis C, Kujath P, Hoffmann M, Bruch HP. Sequential surgical resection of hepatic and pulmo-nary metastases from colorectal cancer. Langenbeck’s Arch Surg. 2010;395:1129e1138.
21. Bellier J, De Wolf J, Hebbar M, et al. Repeated resections of hepatic and pulmonary metastases from colorectal cancer provide long-term survival. World J Surg. 2018;42:1171e1179.
22. Kanemitsu Y, Kato T, Komori K, Fukui T, Mitsudomi T. Validation of a nomogram for predicting overall survival after resection of pulmonary metastases from colorectal cancer at a single cen-ter. World J Surg. 2010;34:2973e2978.
23. Lee BC, Lee HG, Park IJ, et al. The role of radiofrequency ablation for treatment of metachronous isolated hepatic 5-Azacytidine from colorectal cancer. Medicine (Baltim). 2016;95:e4999.
24. Van Cutsem E, Rivera F, Berry S, et al. Safety and efficacy of first-line bevacizumab with FOLFOX, XELOX, FOLFIRI, and flu-oropyrimidines in metastatic colorectal cancer: the BEAT study. Ann Oncol. 2009;20:1842e1847.
Contents lists available at ScienceDirect
journal homepage: www.elsevier.com/locate/biochempharm
Benproperine, an ARPC2 inhibitor, suppresses cancer cell migration and tumor metastasis
Yae Jin Yoona,1, Young-Min Hana,1, Jiyeon Choia,c, Yu-Jin Leea, Jieun Yuna, Su-Kyung Leea, Chang Woo Leea, Jong Soon Kanga, Seung-Wook Chia,b, Jeong Hee Moona, Sangku Leea, Dong Cho Hana,b, , Byoung-Mog Kwona,b, a Laboratory of Chemical Biology and Genomics, Korea Research Institute of Bioscience and Biotechnology, 125 Gwahakro, Daejeon 34141, Republic of Korea b Korea University of Science and Technology in Korea, Daejeon, Republic of Korea c Department of Biology, Chungnam National University, Daejeon 34134, Republic of Korea
Metastasis is the leading cause of cancer mortality and cancer cell migration is an essential stage of metastasis. We identified benproperine (Benp, a clinically used antitussive drug) as an inhibitor of cancer cell migration and an anti-metastatic agent. Benp selectively inhibited cancer cell migration and invasion, which also suppressed metastasis of cancer cells in animal models. Actin-related protein 2/3 complex subunit 2 (ARPC2) was identified as a molecular target of Benp by affinity column chromatography with Benp-tagged Sepharose beads. Benp bound directly to ARPC2 in cells, which was validated by pull-down assay using Benp-biotin and label-free biochemical methods such as the drug affinity responsive target stability (DARTS) and cellular thermal shift assay (CETSA). Benp inhibited Arp2/3 function, showing disruption of lamellipodial structure and inhibition of actin polymerization. Unlike Arp2/3 inhibitors, Benp selectively inhibited the migration of cancer cells but not normal cells. ARPC2-knockdown cancer cells showed defective cell migration and suppressed metastasis in an animal model. Therefore, ARPC2 is a potential target for anti-metastatic therapy, and Benp has the clinical potential to block metastasis. Furthermore, Benp is a useful agent for studying the functions of the Arp2/3 complex in cancer cell migration and metastasis.
In solid tumors, cytostatic drugs have been shown to effectively inhibit the growth of cancer cells but have not been efficacious on cancer metastasis . Metastasis is the leading cause of cancer-related death [2,3] and cancer cell migration is an essential stage of metastasis [4,5]. Therefore, the unmet needs of anti-cancer drug discovery include identifying agents that prevent or block metastasis but that are also safe, selective, and effective. Oncogenic kinase inhibitors targeting signal transduction in cell migration lead to resistance due to highly redundant and bypassable signaling pathways . To overcome drug resistance, migrastatics targeting the modulators or effectors of cancer cell migration and invasion have been proposed as a promising ther-apeutic strategy for treatment of solid tumors [6,7]. Target mechanisms for migrastatics include actin polymerization and actomyosin-mediated contractility . Remodeling of the cytoskeleton plays a pivotal role in