Targeting PECAM-1 for anti-cancer therapy

DeLisser, Horace M.

doi:10.4161/cbt.6.1.3827

Cited by 7 publications

(4 citation statements)

References 18 publications

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“…The inhibition of Forkhead box protein C2 (FOXC2) is reported to restore drug sensitivity in some cancer cells, and reinstate epithelial phenotype to metastatic cells [80,81]. While the cell-adhesion and signaling molecule PECAM-1 is known to modulate resistance to genotoxic chemotherapy such as cisplatin treatment [82].…”

Section: Resultsmentioning

confidence: 99%

Bimetallic titanocene-gold phosphane complexes inhibit invasion, metastasis, and angiogenesis-associated signaling molecules in renal cancer

Elie

Fernández-Gallardo

Curado

et al. 2019

European Journal of Medicinal Chemistry

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Following promising recent in vitro and in vivo studies of the anticancer efficacies of heterometallic titanocene–gold chemotherapeutic candidates against renal cancer, we report here on the synthesis, characterization, stability studies and biological evaluation of a new titanocene complex containing a gold-triethylphosphane fragment [(η-C5H5)2TiMe(μ-mba)Au(PEt3)] (4) Titanofin. The compound is more stable in physiological fluid than those previously reported, and it is highly cytotoxic against a line of human clear cell renal carcinoma. We describe here preliminary mechanistic data for this compound and previously reported [(η-C5H5)2TiMe(μ-mba)Au(PPh3)] (2) Titanocref which displayed remarkable activity in an in vivo mouse model. Mechanistic studies were carried out in the human clear cell renal carcinoma Caki-1 line for the bimetallic compounds [(η-C5H5)2TiMe(μ-mba)Au(PR3)] (PR3 = PPh3 2 Titanocref and PEt3 4 Titanofin), the two monometallic gold derivatives [Au(Hmba)(PR3)] (PR3 = PPh3 1 cref; PEt3 3 fin), titanocene dichloride and Auranofin as controls. These studies indicate that bimetallic compounds Titanocref (2) and Titanofin (4) are more cytotoxic than gold monometallic derivatives (1 and 3) and significantly more cytotoxic than titanocene dichloride while being quite selective. Titanocref (2) and Titanofin (4) inhibit migration, invasion, and angiogenic assembly along with molecular markers associated with these processes such as prometastatic IL(s), MMP(s), TNF-α, and proangiogenic VEGF, FGF-basic. The bimetallic compounds also strongly inhibit the mitochondrial protein TrxR often overexpressed in cancer cells evading apoptosis and also inhibit FOXC2, PECAM-1, and HIF-1α whose overexpression is linked to resistance to genotoxic chemotherapy. In summary, bimetallic titanocene-gold phosphane complexes (Titanocref 2 and Titanofin 4) are very promising candidates for further preclinical evaluations for the treatment of renal cancer.

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Section: Resultsmentioning

confidence: 99%

Bimetallic titanocene-gold phosphane complexes inhibit invasion, metastasis, and angiogenesis-associated signaling molecules in renal cancer

Elie

Fernández-Gallardo

Curado

et al. 2019

European Journal of Medicinal Chemistry

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“…The endothelial specific marker, PECAM-1 (i.e., CD31) (10,12,26), is closely associated with angiogenesis (27), and the vasculature of the TME plays a significant role in the proliferation and invasion of tumor cells. PECAM-1 could be used as a potential therapeutic target on the TME with respect to its activity in the pathogenesis of tumors, including lung cancer (28,29). …”

Section: Discussionmentioning

confidence: 99%

Inhibition of lung tumor growth in nude mice by siRNACD31 targeting PECAM-1

Ouyang

Chen

et al. 2014

Oncology Letters

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Small interfering RNA (siRNA) provides a promising therapeutic approach in the silencing of disease-causing genes. In the present study, the use of 2′-O-methyl-modified siRNA-cluster of differentiation 31 (siRNACD31), with cationic liposome RNA interference (RNAi)-mate as a carrier, effectively silenced the platelet endothelial cell molecule 1 (PECAM-1) gene of murine hemangioendothelioma cells in vitro. In vivo, 2′-O-methyl-modified siRNACD31 carried by RNAi-mate was successfully delivered, targeting the PECAM-1 gene in the vasculature of nude mouse lung carcinoma xenografts. The growth of the lung carcinoma xenografts was inhibited by the 2′-O-methyl-modified siRNACD31 and RNAi-mate complexes, and the expression of the PECAM-1 protein was downregulated, with a simultaneous decrease in vascular endothelial growth factor (VEGF) protein in the lung carcinoma xenografts. 2′-O-methyl-modified siRNACD31-RNAi-mate complexes may provide a potential therapeutic strategy in lung carcinoma treatment. The effect of PECAM-1 on VEGF expression may possibly be attributed to the function of PECAM-1 signal transduction.

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“…58 Not only does the loss or inhibition of PECAM-1 function block tumor growth and angiogenesis, it also may act to normalize pathological vessels ( Figure 2), an activity that facilitates the efficacy of antitumor agents. 52 Anti-PECAM-1 therapy is likely to be well tolerated, since the absence of PECAM-1 does not result in a lethal vascular phenotype, 19 deleterious effects have not been noted in animals treated with anti-PECAM-1 antibodies, [15][16][17] and the absence of PECAM-1 function does not appear to prevent or inhibit dermal wound healing (see above).…”

Section: Discussionmentioning

confidence: 99%