title: CKD712, a synthetic isoquinoline alkaloid, enhances the anti-cancer effects of paclitaxel in MDA-MB-231 cells through regulation of PTEN.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  Cellular proliferation, invasion and apoptosis were assessed by MTT, Western blot analysis, and TUNEL assay.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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: Department of Pharmacology, School of Medicine, Gyeongsang National University, Institute of Health Sciences, Jinju 660-751, Republic of Korea.
authors: Young Min
authors: YM
authors: Kim
authors: Department of Pharmacology, School of Medicine, Gyeongsang National University, Institute of Health Sciences, Jinju 660-751, Republic of Korea.
authors: Konstantin
authors: K
authors: Tsoyi
authors: Department of Pharmacology, School of Medicine, Gyeongsang National University, Institute of Health Sciences, Jinju 660-751, Republic of Korea.
authors: Hwa Jin
authors: HJ
authors: Jang
authors: Department of Pharmacology, School of Medicine, Gyeongsang National University, Institute of Health Sciences, Jinju 660-751, Republic of Korea.
authors: Eun Jung
authors: EJ
authors: Park
authors: Department of Pharmacology, School of Medicine, Gyeongsang National University, Institute of Health Sciences, Jinju 660-751, Republic of Korea.
authors: Sang Won
authors: SW
authors: Park
authors: Department of Pharmacology, School of Medicine, Gyeongsang National University, Institute of Health Sciences, Jinju 660-751, Republic of Korea.
authors: Hye Jung
authors: HJ
authors: Kim
authors: Department of Urology, School of Medicine, Gyeongsang National University, Jinju 660-751, Republic of Korea.
authors: Jeong Seok
authors: JS
authors: Hwa
authors: Department of Pharmacology, School of Medicine, Gyeongsang National University, Institute of Health Sciences, Jinju 660-751, Republic of Korea. Electronic address: kcchang@gnu.kr.
authors: Ki Churl
authors: KC
authors: Chang
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D053148:Caspase 3 / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051550:I-kappa B Kinase; D042361:Mammary Glands, Human / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D051059:PTEN Phosphohydrolase / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D017239:Paclitaxel / Q000494:pharmacology*; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D044005:Tetrahydroisoquinolines / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D051020:bcl-X Protein / Q000235:genetics / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; C494811:BCL2L1 protein, human; D016328:NF-kappa B; D034741:RNA, Small Interfering; D044005:Tetrahydroisoquinolines; D014409:Tumor Necrosis Factor-alpha; C090309:YS 49; D051020:bcl-X Protein; D051550:I-kappa B Kinase; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human; D053148:Caspase 3; D017239:Paclitaxel
keywords: Apoptosis; Breast cancer; Invasion; NF-κB; PTEN; Paclitaxel