Benzophenones and xanthone derivatives from Garcinia schomburgkiana-induced P-glycoprotein overexpression in human colorectal Caco-2 cells via oxidative stress-mediated mechanisms.
BACKGROUND
Up-regulation of P-gp is an adaptive survival mechanism of cancer cells from chemotherapy. Three new phytochemicals including two benzophenones, guttiferone K (GK) and oblongifolin C (OC), and a xanthone, isojacaruebin (ISO), are potential anti-cancer agents. However, the capability of these compounds to increase multidrug-resistance (MDR) through P-gp up-regulation in cancer cells has not been reported.


OBJECTIVE
This study was to investigate the effects of GK, OC and ISO on P-gp up-regulation in colorectal adenocarcinoma cells (Caco-2 cells). In addition, the mechanisms underlying their inductive effect were also determined.


METHODS
The inductive effect of GK, OC and ISO on P-gp expression at transcription level was measured by real-time reverse transcription polymerase chain reaction. The reactive oxygen species production was determined by 2', 7'-dichlorofluorescin diacetate assay. The protein content of P-gp and involvement of mitogen-activated protein kinases (MAPK) pathway was evaluated by western blot analysis.


RESULTS
GK, OC and ISO (50 µM, 24 h) were able to increase the amount of MDR1 mRNA and protein in Caco-2 cells. The presence of N-acetyl-l-cysteine significantly prevented the inductive effect of GK, OC and ISO on MDR1 mRNA level. Moreover, MAPK inhibitors including U0126 (an ERK1/2/MAPK inhibitor) and SB202190 (p38/MAPK inhibitor) suppressed an increase of MDR1 mRNA levels in the cells treated with benzophenones (GK, OC) and xanthone ISO, respectively. These findings were in agreement with the increase of phosphorylated form of either ERK1/2 (p-ERK1/2) or p38 (p-p38) upon treatment of the cells with these three compounds. In addition, OC and ISO, but not GK, increased mRNA of c-Jun level.


CONCLUSIONS
The benzophenones GK, OC and xanthone ISO are likely MDR inducers through up-regulation of P-gp expression at transcription level. Their molecular mechanisms involve oxidative stress-mediated activation of MAPK signaling pathway.
Inter-Department Program of Pharmacology, Graduate School, Chulalongkorn University, Bangkok 10330, Thailand.
Cherdsak
C
Boonyong
Department of Pharmacognosy and Pharmaceutical Botany, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok 10330, Thailand.
Chutichot
C
Pattamadilok
Department of Pharmacognosy and Pharmaceutical Botany, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok 10330, Thailand.
Rutt
R
Suttisri
Department of Pharmacology and Physiology, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok 10330, Thailand. Electronic address: suree.j@pharm.chula.ac.th.
Suree
S
Jianmongkol
D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics / Q000378:metabolism*; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D001577:Benzophenones / Q000494:pharmacology*; D018938:Caco-2 Cells / Q000187:drug effects*; D029760:Garcinia / Q000737:chemistry*; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D018384:Oxidative Stress; D010936:Plant Extracts / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D044004:Xanthones / Q000494:pharmacology*
D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D001577:Benzophenones; D010936:Plant Extracts; D044004:Xanthones; C009689:xanthone
Guttiferone K; Isojacaruebin; MAPKs; Oblongifolin C; Oxidative stress; P-gp