Berberine and Curcumin Target Survivin and STAT3 in Gastric Cancer Cells and Synergize Actions of Standard Chemotherapeutic 5-Fluorouracil.
Aberrantly expressed survivin and STAT3 signaling have emerged as major determinants of chemoresistance in gastric cancer. We evaluated effects of potent herbal derivatives curcumin, berberine, and quercetin on STAT3 signaling, survivin expression, and response to 5-fluorouracil (5-FU) treatment in gastric cancer cells (AGS). Cytotoxic and inhibitory effects of berberine, curcumin, and quercetin alone or in combination with 5-FU were examined by MTT assay, and their effect on survivin, STAT3, and the phosphorylated active STAT3 (pSTAT3) expression was examined by western blotting. Effect of these herbal derivatives on STAT3 DNA binding activity was measured by electrophoretic mobility shift assay. Curcumin, berberine, and quercetin effectively downregulated pSTAT3 levels, survivin expression, and gastric cancer cells viability in a dose-dependent manner (with corresponding IC50 values of 40.3μM, 29.2μM and 37.5μM, respectively). Berberine was more effective in inhibiting survivin expression as compared to other herbal agents. 5-FU in combination with berberine or curcumin showed a synergistic inhibition of survivin and STAT3 level resulting in enhanced cell death in gastric cancer cells. Overall, our data suggest use of berberine and curcumin as adjunct therapeutics to overcome chemoresistance during treatment of gastric malignancies.
a Division of Molecular Oncology , Institute of Cytology and Preventive Oncology, Noida, India and Center for Biotechnology, University of Allahabad , Allahabad , India.
Arvind
A
Pandey
b Division of Molecular Oncology , Institute of Cytology and Preventive Oncology , Noida , India.
Kanchan
K
Vishnoi
b Division of Molecular Oncology , Institute of Cytology and Preventive Oncology , Noida , India.
Sutapa
S
Mahata
e Clinical Cancer Prevention-Research , UT MD Anderson Cancer Center , Houston , Texas , USA.
Satyendra Chandra
SC
Tripathi
c Department of Gastroenterology , MLN Medical College , Allahabad , India.
Sri Prakash
SP
Misra
d Department of Pathology , MLN Medical College , Allahabad , India.
Vatsala
V
Misra
b Division of Molecular Oncology , Institute of Cytology and Preventive Oncology , Noida , India.
Ravi
R
Mehrotra
c Department of Gastroenterology , MLN Medical College , Allahabad , India.
Manisha
M
Dwivedi
b Division of Molecular Oncology , Institute of Cytology and Preventive Oncology , Noida , India.
Alok C
AC
Bharti
D001599:Berberine / Q000494:pharmacology* / Q000627:therapeutic use; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D003474:Curcumin / Q000494:pharmacology* / Q000627:therapeutic use; D004247:DNA / Q000378:metabolism; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004357:Drug Synergism; D005472:Fluorouracil / Q000627:therapeutic use*; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000037:antagonists & inhibitors* / Q000187:drug effects; D016328:NF-kappa B / Q000378:metabolism; D011794:Quercetin / Q000494:pharmacology; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors* / Q000187:drug effects / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013274:Stomach Neoplasms / Q000188:drug therapy*; D000077022:Survivin
C107489:BIRC5 protein, human; D051034:Inhibitor of Apoptosis Proteins; D016328:NF-kappa B; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D000077022:Survivin; D001599:Berberine; D004247:DNA; D011794:Quercetin; D003474:Curcumin; D005472:Fluorouracil