Abstract
Ovarian carcinoma, the most lethal gynecological cancer, is characterized by late diagnosis, with drug resistance limiting the efficacy of platinum-based therapy. Since some integrins are upregulated in cancer, including ovarian carcinoma, they represent a potential target for drug delivery. Receptor tyrosine kinases are also deregulated in cancer and their expression has been associated with drug resistance. Here, the antitumor effects of three conjugates possessing a selective binder of the extracellular portion of integrin αVβ3 covalently linked to the tyrosine kinase inhibitor sunitinib were investigated in cisplatin-sensitive and -resistant ovarian carcinoma cells expressing both tyrosine kinase VEGFR2 and αVβ3 at different levels. We found that one of the three compounds was active in inhibiting the growth of both drug-sensitive and -resistant cells in the micromolar range with a slightly increased potency in resistant cells as compared to sunitinib. The same compound markedly impaired cell migratory and invasive abilities and reduced paxillin phosphorylation. Antitumor activity studies in IGROV-1/Pt1 cells xenografted in nude mice revealed a striking activity of this conjugate versus sunitinib. Taken together, our results support the interest of integrin-targeted sunitinib conjugates for the treatment of drug-resistant tumors.
Highlights
Ovarian carcinoma is the most lethal gynecological cancer as it is often diagnosed at an advanced stage [1]
Small conjugates represent represent aa recent recent class class of of drugs Small molecule-drug molecule-drug conjugates drugs with with the the potential potential to to target target tumor-specific or overexpressed antigens and some integrin subtypes such tumor-specific or overexpressed antigens [11,12,22,23]. Since both receptor tyrosine kinases (RTKs) and some integrin subtypes as α β are overexpressed in cancer cells, agents directed to both these targets appear to be extremely suchV as3 αVβ3 are overexpressed in cancer cells, agents directed to both these targets appear to be promising, taking into taking accountinto the account tumor targeting properties integrin ligands
The A2780 cell line, exhibiting detectable levels of VEGFR2 and levels of αV β3 lower than IGROV-1/Pt1 cells, was examined in cell migration and invasion assays, and we found that, again, conjugates 1–3 displayed the capability to inhibit cell aggressiveness, to a reduced extent than in IGROV-1/Pt1 cells. These results suggest that this class of compounds might be useful in ovarian carcinoma as novel therapeutic agents, but it appears to be important to consider the level of expression of VEGFR2 and αV β3 to target cells coexpressing both targets
Summary
Ovarian carcinoma is the most lethal gynecological cancer as it is often diagnosed at an advanced stage [1]. Late diagnosis makes the disease difficult to cure in spite of the initial efficacy of platinum-based treatment [2,3]. The pathways sustaining drug resistance of ovarian carcinoma are multiple and involve, among the diverse factors, drug accumulation impairment, loss of DNA mismatch repair, increased nucleotide excision repair, and hyperactivation of receptor tyrosine kinases (RTKs) [5,6,7]. Such receptors, frequently deregulated in cancer, are implicated in the Cancers 2019, 11, 531; doi:10.3390/cancers11040531 www.mdpi.com/journal/cancers
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