A therapeutically relevant, 3,3′-diindolylmethane derivative NGD16 attenuates angiogenesis by targeting glucose regulated protein, 78 kDa (GRP78)

• NGD16 is a cytotoxic anticancer agent.
• NGD16 inhibits in vivo and ex vivo angiogenesis.
• NGD16 alters GRP78 signaling pathway in angiogenesis.
• NGD16 confers a desirable pharmacokinetic profile.

Angiogenesis remain a critical procedure for tumor progression and malignancy. Anticancer agents targeting angiogenic cascades have been proved to be an effective strategy in the field of cancer therapeutics. The current study aims to explore the mechanistic prevention of angiogenesis and cancer cell proliferation by 1,1′-β-d-glucopyranosyl-3,3′-bis(5-bromoindolyl)-octyl methane (NGD16), a novel N-glycosylated derivative of 3,3′-diindolylmethane (DIM). NGD16 suppressed the viability of prostate cancer (PC-3), pancreatic adenocarcinoma (MiaPaca-2), colorectal cancer (COLO-205) and human umbilical vein endothelial cells (HUVECs) effectively with IC50 values 0.8 μM, 2.8 μM, 5.3 μM and 2.5 μM respectively. Abrogation of angiogenesis by NGD16 was promising in in vivo mouse Matrigel plug assay as well as in ex vivo sprouting of rat thoracic aorta. At the molecular level, NGD16 inhibited the expression of glucose regulated protein, 78 kDa (GRP78), vascular endothelial growth factor receptor-2 (VEGFR2) and matrix metalloproteinase-9 (MMP-9) expression, the main mediators of angiogenesis and neovessel formation. Overexpression of GRP78 upregulated the expression of MMP-9 and VEGFR2 in PC-3 and HUVECs. Antibody blocking of GRP78 further potentiated NGD16 in attenuating angiogenesis through inhibition of MMP-9. NGD16 depicted its promising biodistribution profile in a pharmacokinetic study with 46.9% intraperitoneal bioavailability. Our findings suggest NGD16 is a potent inhibitor of neo-angiogenesis with a desirable pharmacokinetic profile, which can be taken forward in its development as an anticancer drug.

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