Research Paper Volume 11, Issue 18 pp 7780—7795

Sulfated polysaccharide of Sepiella maindroni ink targets Akt and overcomes resistance to the FGFR inhibitor AZD4547 in bladder cancer

Liping Shan 1, , Wei Liu 2, , Yunhong Zhan 1, ,

  • 1 Department of Urology, Shengjing Hospital, China Medical University, Shenyang, Liaoning 110004, China
  • 2 Emergency Department, First Hospital of China Medical University, Shenyang, Liaoning, China

received: July 13, 2019 ; accepted: September 9, 2019 ; published: September 23, 2019 ;

https://doi.org/10.18632/aging.102286
How to Cite

Copyright © 2019 Shan et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Abstract

Rapid appearance of resistance to fibroblast growth factor receptor (FGFR) inhibitors hampers targeted regimens in bladder cancer. In the present study, we evaluated whether SIP-SII, a sulphated derivative of the polysaccharide in Sepiella maindroni (spineless cuttlefish) ink used in traditional Chinese medicine, could attenuate resistance to FGFR inhibition in bladder cancer cells. In vitro assays indicated that SIP-SII reduced cell viability and migration, restricted cell cycle progression, and increased apoptosis in parallel with decreased AKT phosphorylation and downregulation of CDK4, MMP2, and Bcl-2 in RT112 and JMSU1 cells. Synergistic effects on cell viability were observed when SIP-SII was combined with the small-molecule FGFR inhibitor AZD4547. Specific Akt targeting by SIP-SII was suggested by the fact that neither Akt knockdown nor the selective PI3K inhibitor BKM120 enhanced the inhibitory effects of SIP-II, while expression of a constitutively active Akt mutant rescued SIP-SII effects. Furthermore, subcutaneous transplantation of RT112 xenografts confirmed the superiority and tolerability of combined SIP-SII and AZD4547 administration over monotherapy regimens. The present study thus provides pre-clinical evidence of the ability of SIP-SII to improve FGFR-targeted therapies for bladder cancer by inhibiting Akt.

Abbreviations

RTK: receptor tyrosine kinase; EGFR: epidermal growth factor receptor; FGFR: fibroblast growth factor receptor; PI3K: phosphatidylinositol-3-kinase; AKT: protein kinase B; mTOR: mammalian target of rapamycin; MAPK: mitogen-activated protein kinase; ERK: extracellular-signal-regulated kinase; RAS: RAS type GTPase family; JAK: tyrosine-protein kinase JAK; STAT: signal transducer and activator of transcription; MET: MET protooncogene, receptor tyrosine kinase; Bcl-2: apoptosis regulator Bcl-2; CDK4: cyclin-dependent kinase 4; MMP2: matrix metallopeptidase 2; SIP-SII: sulfated polysaccharide of Sepiella maindroni ink.