title: A therapeutically relevant, 3,3'-diindolylmethane derivative NGD16 attenuates angiogenesis by targeting glucose regulated protein, 78kDa (GRP78).
abstract: 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.
authors: Academy of Scientific and Innovative Research (AcSIR), CSIR-Indian Institute of Integrative Medicine, Jammu, India; Cancer Pharmacology Division, CSIR-Indian Institute of Integrative Medicine, Jammu, India.
authors: Debasis
authors: D
authors: Nayak
authors: Cancer Pharmacology Division, CSIR-Indian Institute of Integrative Medicine, Jammu, India.
authors: Hina
authors: H
authors: Amin
authors: Cancer Pharmacology Division, CSIR-Indian Institute of Integrative Medicine, Jammu, India.
authors: Bilal
authors: B
authors: Rah
authors: Cancer Pharmacology Division, CSIR-Indian Institute of Integrative Medicine, Jammu, India.
authors: Reyaz
authors: R
authors: Ur Rasool
authors: Natural Product Chemistry Division, CSIR-Indian Institute of Integrative Medicine, Jammu, India.
authors: Deepak
authors: D
authors: Sharma
authors: Natural Product Chemistry Division, CSIR-Indian Institute of Integrative Medicine, Jammu, India.
authors: Ajai Prakash
authors: AP
authors: Gupta
authors: Natural Product Chemistry Division, CSIR-Indian Institute of Integrative Medicine, Jammu, India.
authors: Manoj
authors: M
authors: Kushwaha
authors: Natural Product Chemistry Division, CSIR-Indian Institute of Integrative Medicine, Jammu, India.
authors: Debaraj
authors: D
authors: Mukherjee
authors: Academy of Scientific and Innovative Research (AcSIR), CSIR-Indian Institute of Integrative Medicine, Jammu, India; Cancer Pharmacology Division, CSIR-Indian Institute of Integrative Medicine, Jammu, India. Electronic address: agoswami@iiim.ac.in.
authors: Anindya
authors: A
authors: Goswami
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D045744:Cell Line, Tumor / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D000091342:Endoplasmic Reticulum Chaperone BiP; D006360:Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects; D006801:Humans; D007211:Indoles / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D008297:Male; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D058990:Molecular Targeted Therapy; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000378:metabolism / Q000517:prevention & control*; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000473:pathology; D017208:Rats, Wistar; D015398:Signal Transduction / Q000187:drug effects
chemical_list: C000598856:1,1'-beta-D-glucopyranosyl-3,3'-bis(5-bromoindolyl)-octyl methane; D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; D006360:Heat-Shock Proteins; C000717248:Hspa5 protein, mouse; D007211:Indoles; C016392:3,3'-diindolylmethane
keywords: Angiogenesis; GRP78; MMP-9; NGD16; Pharmacokinetics