Silibinin and Paclitaxel Cotreatment Significantly Suppress the Activity and Lung Metastasis of Triple Negative 4T1 Mammary Tumor Cell in Mice

Bing-Ying Ho; Chun-Hung Lin; Maria Karmella Apaya; Wen-Wan Chao; Lie-Fen Shyur

doi:10.1016/s2225-4110(16)30116-x

Silibinin and Paclitaxel Cotreatment Significantly Suppress the Activity and Lung Metastasis of Triple Negative 4T1 Mammary Tumor Cell in Mice

J Tradit Complement Med. 2012 Oct;2(4):301-11. doi: 10.1016/s2225-4110(16)30116-x.

Authors

Bing-Ying Ho¹, Chun-Hung Lin², Maria Karmella Apaya¹, Wen-Wan Chao¹, Lie-Fen Shyur³

Affiliations

¹ Agricultural Biotechnology Research Center, Academia Sinica, Taipei 115, Taiwan.
² Agricultural Biotechnology Research Center, Academia Sinica, Taipei 115, Taiwan ; Department of Biochemical Science and Technology, National Taiwan University, Taipei 106, Taiwan.
³ Agricultural Biotechnology Research Center, Academia Sinica, Taipei 115, Taiwan ; Department of Biochemical Science and Technology, National Taiwan University, Taipei 106, Taiwan ; Graduate Institute of Pharmacognosy, Taipei Medical University, Taipei 110, Taiwan.

Abstract

The in vitro and in vivo bioactivities of silibinin (SB), paclitaxel (PTX) and SB and PTX in combination (SB+PTX) against murine metastatic mammary 4T1 cancer cell line were investigated. Isobologram and combination index (CI) analyses showed that SB and PTX can function synergistically in the inhibition of 4T1 cell proliferation with a CI value < 1. Both SB and PTX alone or SB+PTX treatment inhibited 4T1 cell migration and motility possibly through downregulation of the serpin protease nexin-1 (PN-1) and N-cadherin expression, inhibition of matrix metalloprotease (MMP)-9 activity, and upregulation of E-cadherin. Flow cytometry and Western blot analyses demonstrated that both drugs deregulated cell-cycle mediators and induced apoptosis in 4T1 cells. A real-time in vivo bioluminescence imaging system to monitor the breast cancer cell metastasis in syngeneic BALB/c mice was established using a stable 4T1(pGL-COX-2/Luc) cell clone carrying a COX-2 promoter driven-luciferase reporter gene. In vivo study using the allograft 4T1(pGL-COX-2/Luc) metastatic mouse model indicated that SB co-treated with PTX can significantly suppress lung metastasis of 4T1 cells likely through inhibiting cell proliferation and angiogenesis. Together, this study demonstrates that SB could act synergistically with PTX in 4T1 cells, providing a therapeutic option for highly metastatic triple negative breast cancer.

Keywords: Lung metastasis; Paclitaxel; Silibinin; Synergistic effect; Triple negative breast cancer.