αvβ3 Integrin Antagonists Enhance Chemotherapy Response in an Orthotopic Pancreatic Cancer Model

Abstract

Pancreatic cancer decreases survival time and quality of life because of drug resistance and peripheral neuropathy during conventional treatment. This study was undertaken to investigate whether avb3 integrin receptor antagonist compounds NDAT and XT199 can suppress the development of cisplatin resistance and cisplatin-induced peripheral neuropathy in an orthotopic pancreatic SUIT2-luc cancer cell mouse model. Anticancer effects of these compounds and their combination with cisplatin were assessed in this tumor mouse model with bioluminescent signaling and histopathology, and a cytokine assay was used to examine expression of inflammatory cytokines IL-1b, IL-6, IL-10, and TNF-a from plasma samples. To determine the neuroprotective effects of the compounds on cisplatin-induced peripheral neuropathy, behavioral hind-limb posture of the mice was evaluated. The combination therapy of NDAT or XT199 with cisplatin elicited greater inhibition of tumor growth and increased tumor necrosis compared to cisplatin alone. NDAT and XT199 in combination with cisplatin significantly decreased expression of proinflammatory cytokines IL-1b, IL-6, and TNF-a and significantly increased expression of anti-inflammatory cytokine IL-10 in comparison to cisplatin alone. Cisplatin-treated groups showed stocking-glove hind-limb posture, whereas NDAT and XT199 with cisplatintreated groups displayed normal hind-limb posture. Results clearly suggest that NDAT and XT199 treatment with cisplatin that inactivates NF-kB may contribute to increased antitumor and anti-inflammatory efficacy as well as alleviate cisplatin-mediated loss of motor function in this pancreatic tumor mouse model.

RETRACTED: Anti-Cancer Activities of Thyrointegrin αvβ3 Antagonist Mono- and Bis-Triazole Tetraiodothyroacetic Acid Conjugated via Polyethylene Glycols in Glioblastoma

“…The luminescent signals of the single molecular target on αvβ3, the target that, when activated by chemically modified tetrac, regulates a network of intracellular signaling pathways and plasma membrane functions, and further, controls specific gene transcription and cell surface vascular growth factor receptor functions that are highly relevant to cancer and cancer-linked angiogenesis. Previous studies showed that αvβ3 antagonists’ multivalency results in increased binding affinity, which then improved targeted therapeutic delivery [ 11 , 28 , 29 ]. However, despite many studies over years, there are no reports that have demonstrated improved therapeutic effectiveness of dimer αvβ3 antagonists over monomer αvβ3 antagonists.…”

Actions of Thyroid Hormones on Thyroid Cancers

“…Overexpression and activation of the protein renders tumor cells susceptible to actions of T4 to stimulate proliferation, to support cancer cell defense pathways such as anti-apoptosis (7) and radioresistance (8), and to enhance cancer-related angiogenesis (2,3,9,10). Preclinical studies have shown a variety of tumor cells to proliferate in response to physiological concentrations of T4 (11)(12)(13)(14). A derivative of T4, tetraiodothyroacetic acid (tetrac), blocks actions of T4 on tumor cell avb3 (3).…”

Integrin alpha V (ITGAV) expression in esophageal adenocarcinoma is associated with shortened overall-survival

“…In particular, epithelial-mesenchymal transition (EMT), migration, cell proliferation and chemoresistance have been described as ITGAV mediated effects 29 . ITGAV could be identified as EMT marker in breast, colon and pancreatic carcinoma 30 – 32 . It was shown that the combination of integrin alpha V/beta 6 expression is closely correlated with the expression of other EMT markers, such as ZEB1 and ZEB2, and this could be explained as a possible pathway for ITAGV associated tumor cell detachment from rigid cell formation and therefore tumor progression in terms of metastatic spread 24 .…”