Young Min Kim1, Konstantin Tsoyi1, Hwa Jin Jang1, Eun Jung Park1, Sang Won Park1, Hye Jung Kim1, Jeong Seok Hwa2, Ki Churl Chang3. 1. Department of Pharmacology, School of Medicine, Gyeongsang National University, Institute of Health Sciences, Jinju 660-751, Republic of Korea. 2. Department of Urology, School of Medicine, Gyeongsang National University, Jinju 660-751, Republic of Korea. 3. Department of Pharmacology, School of Medicine, Gyeongsang National University, Institute of Health Sciences, Jinju 660-751, Republic of Korea. Electronic address: kcchang@gnu.kr.
Abstract
AIMS: It has been reported that in human glioblastoma cells, phosphotase and tensin homolog (PTEN) positive cells are more prone to paclitaxel-induced apoptosis than PTEN-negative cells. We investigated whether (S)-1-(α-naphthylmethyl)-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline (CKD712) enhances the therapeutic effects of paclitaxel (including effects on cellular proliferation, invasion and apoptosis) in MDA-MB-231 cells through PTEN and NF-κB activity. MAIN METHODS: Cellular proliferation, invasion and apoptosis were assessed by MTT, Western blot analysis, and TUNEL assay. KEY FINDINGS: The combination of paclitaxel and CKD712 significantly decreased cell growth, invasion and MMP-9 expression/activity compared with paclitaxel alone. CKD712 enhanced the inhibition of cell growth and invasion in response to paclitaxel in scramble siRNA-transfected, but not siPTEN-transfected cells. CKD712 significantly increased the levels of apoptosis induced by paclitaxel and this apoptosis was accompanied by reduced expression of Bcl-xL but increased activation of caspase-3. TUNEL assay further confirms that CKD712 enhanced the apoptotic effect of paclitaxel. Interestingly, over-expression of PTEN decreased phosphorylation of IκBα and NF-κB expression in the nucleus, indicating that PTEN modifies NF-κB activity in MDA-MB-231 cells. CKD712 treatment also significantly reduced expression of p-IκB and NF-κB activity in TNF-α activated cells. SIGNIFICANCE: CKD712 strongly enhances the anti-cancer effects (proliferation, invasion, and apoptosis) of paclitaxel on MDA-MB-231 cells by regulating PTEN and NF-κB activity.
AIMS: It has been reported that in humanglioblastoma cells, phosphotase and tensin homolog (PTEN) positive cells are more prone to paclitaxel-induced apoptosis than PTEN-negative cells. We investigated whether (S)-1-(α-naphthylmethyl)-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline (CKD712) enhances the therapeutic effects of paclitaxel (including effects on cellular proliferation, invasion and apoptosis) in MDA-MB-231 cells through PTEN and NF-κB activity. MAIN METHODS: Cellular proliferation, invasion and apoptosis were assessed by MTT, Western blot analysis, and TUNEL assay. KEY FINDINGS: The combination of paclitaxel and CKD712 significantly decreased cell growth, invasion and MMP-9 expression/activity compared with paclitaxel alone. CKD712 enhanced the inhibition of cell growth and invasion in response to paclitaxel in scramble siRNA-transfected, but not siPTEN-transfected cells. CKD712 significantly increased the levels of apoptosis induced by paclitaxel and this apoptosis was accompanied by reduced expression of Bcl-xL but increased activation of caspase-3. TUNEL assay further confirms that CKD712 enhanced the apoptotic effect of paclitaxel. Interestingly, over-expression of PTEN decreased phosphorylation of IκBα and NF-κB expression in the nucleus, indicating that PTEN modifies NF-κB activity in MDA-MB-231 cells. CKD712 treatment also significantly reduced expression of p-IκB and NF-κB activity in TNF-α activated cells. SIGNIFICANCE: CKD712 strongly enhances the anti-cancer effects (proliferation, invasion, and apoptosis) of paclitaxel on MDA-MB-231 cells by regulating PTEN and NF-κB activity.
Authors: Konstantin Tsoyi; Juan C Osorio; Sarah G Chu; Isis E Fernandez; Sergio Poli De Frias; Lynette Sholl; Ye Cui; Carmen S Tellez; Jill M Siegfried; Steven A Belinsky; Mark A Perrella; Souheil El-Chemaly; Ivan O Rosas Journal: Am J Respir Cell Mol Biol Date: 2019-06 Impact factor: 6.914