title: Synergistic combination of YS-1 and adriamycin inhibits human renal cancer through ERK1/2 signaling pathway in vitro and in vivo.
abstract: Adriamycin (ADM) is a principal drug for the treatment of renal cell cancer (RCC). Due to its limited response and high renal and cardiac toxicity, synergistic effects of ADM in combination with other drugs have been widely researched. In this study, we found the combination between YS-1 and ADM, performed higher anticancer activity on 786-O human RCC cells in vitro and in vivo, than that reported on its anti-angiogenesis effect compared with monotherapy of ADM. Our data showed that when combined with ADM, YS-1 promoted the sensitivity of 786-O cells to ADM. The combination of YS-1 and ADM also inhibited cell proliferation, but without affecting cell apoptosis. We found that ADM monotherapy treatment notably upregulated the activity of extracellular signal-regulated kinase ERK1 and ERK2 (ERK1/2), but when combined with YS-1, the p-ERK1/2 level was reduced; then inhibited the Ras/Raf/MEK pathway. Additionally, the synergistic effects on cell cycle arrest inhibition were eliminated when ERK1/2 was silenced using siRNA. Our combination therapy of YS-1 with ADM showed the strongest antitumor effects in vivo (inhibition ratio: 5 mg/kg YS-1 combined with 1 mg/kg ADM, 68.19%) in comparison with individual effects (inhibition ratio: 5 mg/kg YS-1, 30.07%; 1 mg/kg ADM, 50.42%). Collectively, these findings indicated that YS-1 did not only enhance the ability of ADM to inhibit tumor proliferation, but also reduce the renal toxicity to protect the normal renal tissues.
authors.affiliation: Jiangsu Center for Pharmacodynamics Research and Evaluation, China Pharmaceutical University, Nanjing, Jiangsu 210009, P.R. China.
authors.forename: Xiaowen
authors.initials: X
authors.lastname: Yu
authors.affiliation: Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical University, Nanjing, Jiangsu 210009, P.R. China.
authors.forename: Qingqing
authors.initials: Q
authors.lastname: Yang
authors.affiliation: Jiangsu Center for Pharmacodynamics Research and Evaluation, China Pharmaceutical University, Nanjing, Jiangsu 210009, P.R. China.
authors.forename: Sensen
authors.initials: S
authors.lastname: Lin
authors.affiliation: Jiangsu Center for Pharmacodynamics Research and Evaluation, China Pharmaceutical University, Nanjing, Jiangsu 210009, P.R. China.
authors.forename: Shengtao
authors.initials: S
authors.lastname: Yuan
authors.affiliation: Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical University, Nanjing, Jiangsu 210009, P.R. China.
authors.forename: Li
authors.initials: L
authors.lastname: Sun
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D003131:Combined Modality Therapy; D004317:Doxorubicin / Q000494:pharmacology*; D004357:Drug Synergism; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D007680:Kidney Neoplasms / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D024101:Mitochondrial Proteins / Q000494:pharmacology*; D010444:Peptide Elongation Factor Tu / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D011994:Recombinant Proteins / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D000903:Antibiotics, Antineoplastic; D024101:Mitochondrial Proteins; D012333:RNA, Messenger; D011994:Recombinant Proteins; C091648:TUFM protein, human; D004317:Doxorubicin; D010444:Peptide Elongation Factor Tu