TY - JOUR
T1 - Isorhamnetin augments the anti-tumor effect of capeciatbine through the negative regulation of NF-κB signaling cascade in gastric cancer
AU - Manu, Kanjoormana A.
AU - Shanmugam, Muthu K.
AU - Ramachandran, Lalitha
AU - Li, Feng
AU - Siveen, Kodappully Sivaraman
AU - Chinnathambi, Arunachalam
AU - Zayed, M. E.
AU - Alharbi, Sulaiman Ali
AU - Arfuso, Frank
AU - Kumar, Alan Prem
AU - Ahn, Kwang Seok
AU - Sethi, Gautam
N1 - Funding Information:
This work was supported by NUHS Bench to Bedside to Product grant to GS. The Deanship of Scientific Research, College of Science Research Centre, King Saud University , Kingdom of Saudi Arabia also supported the work. KSA was supported by the Korea Science and Engineering Foundation (KOSEF) grant funded by the Korean Ministry of Education, Science and Technology (MoEST) (No. 2011-0006220 ). APK was supported by grants from the Singapore Ministry of Education Tier 2 [ MOE2012-T2-2-139 ], NUHS Bench-to-Bedside-To-Product [ R-184-000-243-515 ] and Cancer Science Institute of Singapore , Experimental Therapeutics I Program [ R-713-001-011-271 ].
Publisher Copyright:
© 2015 Elsevier Ireland Ltd.
PY - 2015/7/10
Y1 - 2015/7/10
N2 - Development of drug resistance to standard chemotherapy is a common phenomenon that leads to poor prognosis in patients. Thus, novel agents that can attenuate chemoresistance are urgently needed. Therefore, we analyzed whether isorhamnetin (IH), a 3'-O-methylated metabolite of quercetin, can enhance the potential efficacy of capecitabine in gastric cancer. The potential effect of IH on viability was analyzed by MTT assay, apoptosis by flow cytometric analysis, and NF-κB activation by DNA binding as well as Western blot assays. The in vivo effect of IH was also examined on the growth of subcutaneously implanted tumors in nude mice. IH inhibited the viability, potentiated the apoptotic effects of capecitabine, abrogated NF-κB activation, and suppressed the expression of various NF-κB regulated gene products in tumor cells. In a gastric cancer xenograft model, administration of IH alone (1 mg/kg body weight, i.p.) significantly suppressed the tumor growth alone as well as in combination with capecitabine. IH further reduced NF-κB activation and the expression of various proliferative and oncogenic biomarkers in tumor tissues. Overall, our results demonstrate that IH can significantly enhance the anti-tumor effects of capecitabine through the negative regulation of NF-κB regulated oncogenic genes.
AB - Development of drug resistance to standard chemotherapy is a common phenomenon that leads to poor prognosis in patients. Thus, novel agents that can attenuate chemoresistance are urgently needed. Therefore, we analyzed whether isorhamnetin (IH), a 3'-O-methylated metabolite of quercetin, can enhance the potential efficacy of capecitabine in gastric cancer. The potential effect of IH on viability was analyzed by MTT assay, apoptosis by flow cytometric analysis, and NF-κB activation by DNA binding as well as Western blot assays. The in vivo effect of IH was also examined on the growth of subcutaneously implanted tumors in nude mice. IH inhibited the viability, potentiated the apoptotic effects of capecitabine, abrogated NF-κB activation, and suppressed the expression of various NF-κB regulated gene products in tumor cells. In a gastric cancer xenograft model, administration of IH alone (1 mg/kg body weight, i.p.) significantly suppressed the tumor growth alone as well as in combination with capecitabine. IH further reduced NF-κB activation and the expression of various proliferative and oncogenic biomarkers in tumor tissues. Overall, our results demonstrate that IH can significantly enhance the anti-tumor effects of capecitabine through the negative regulation of NF-κB regulated oncogenic genes.
KW - Capecitabine
KW - Gastric cancer
KW - Isorhamnetin
KW - NF-κB
UR - http://www.scopus.com/inward/record.url?scp=84929044594&partnerID=8YFLogxK
U2 - 10.1016/j.canlet.2015.03.033
DO - 10.1016/j.canlet.2015.03.033
M3 - Article
C2 - 25827070
AN - SCOPUS:84929044594
SN - 0304-3835
VL - 363
SP - 28
EP - 36
JO - Cancer Letters
JF - Cancer Letters
IS - 1
ER -