title: Cinnamaldehyde derivative (CB-PIC) sensitizes chemo-resistant cancer cells to drug-induced apoptosis via suppression of MDR1 and its upstream STAT3 and AKT signalling.
abstract: OBJECTIVE
  Our group reported that cinnamaldehyde derivative, (E)-4-((2-(3-oxopop-1-enyl)phenoxy)methyl)pyridinium malonic acid (CB-PIC) induced apoptosis in hypoxic SW620 colorectal cancer cells via activation of AMP-activated protein kinase (AMPK) and extracellular signal regulated kinase (ERK). Herein, sensitizing effect of CB-PIC was investigated in resistant cancer cells such as paclitaxel (PT) resistant lung cancer cells (H460/PT), and Adriamycin (Adr) resistant breast cancer (MCF7/Adr) and colon cancer (HCT15/cos) cells.
  
  
  METHODS
  Various drug resistant cell lines were treated with CB-PIC, and the signalling pathway and functional assay were explored by Western blot, Rhodamine assay, FACS, RT-PCR and MTT assay.
  
  
  RESULTS
  We found that CB-PIC effectively exerted cytotoxicity, increased sub G1 population and the cleaved form of poly (ADP-ribose) polymerase (PARP) and caspase 9 in drug resistant cancer cells. Furthermore, CB-PIC sensitized resistant cancer cells to adriamycin via downregulation of survival proteins such as survivin, Bcl-xL and Bcl-2, along with MDR1 suppression leading to accumulation of drug in the intracellular region. Of note, CB-PIC transcriptionally decreased MDR1 expression via suppression of STAT3 and AKT signalling in three resistant cancer cells with highly expressed P-glycoprotein. Nonetheless, CB-PIC did not affect transport activity of P-glycoprotein in a short time efflux assay, while epigallocatechin gallate (EGCG) accumulated Rhodamine 123 into intracellular region of cell by direct inhibition of MDR1 transport activity.
  
  
  CONCLUSIONS
  These data demonstrate that CB-PIC suppresses the P-glycoprotein expression through inhibition of STAT3 and AKT signalling to overcome drug resistance in chemo-resistant cancer cells as a potent chemotherapeutic sensitizer.
authors.affiliation: College of Korean Medicine, Kyung Hee University, Seoul, South Korea.
authors.forename: Miyong
authors.initials: M
authors.lastname: Yun
authors.forename: Duckgue
authors.initials: D
authors.lastname: Lee
authors.forename: Moon-Nyeo
authors.initials: MN
authors.lastname: Park
authors.forename: Eun-Ok
authors.initials: EO
authors.lastname: Kim
authors.forename: Eun Jung
authors.initials: EJ
authors.lastname: Sohn
authors.forename: Byung-Mog
authors.initials: BM
authors.lastname: Kwon
authors.forename: Sung-Hoon
authors.initials: SH
authors.lastname: Kim
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics / Q000378:metabolism*; D000171:Acrolein / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D053453:Caspase 9 / Q000378:metabolism; D045744:Cell Line, Tumor; D015536:Down-Regulation / Q000187:drug effects; D004317:Doxorubicin / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D004357:Drug Synergism; D059585:G1 Phase Cell Cycle Checkpoints / Q000187:drug effects; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000235:genetics / Q000378:metabolism; D061986:MCF-7 Cells; D010766:Phosphorylation / Q000187:drug effects; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D011725:Pyridines / Q000737:chemistry / Q000494:pharmacology*; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D000077022:Survivin; D051020:bcl-X Protein / Q000235:genetics / Q000378:metabolism
chemical_list: C000603763:4-((2-(3-oxoprop-1-enyl)phenoxy)methyl)pyridine; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; C107489:BIRC5 protein, human; D051034:Inhibitor of Apoptosis Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D011725:Pyridines; D050796:STAT3 Transcription Factor; D000077022:Survivin; D051020:bcl-X Protein; D000171:Acrolein; D004317:Doxorubicin; D011065:Poly(ADP-ribose) Polymerases; D051057:Proto-Oncogene Proteins c-akt; D053453:Caspase 9; C012843:cinnamaldehyde