CKD-516 displays vascular disrupting properties and enhances anti-tumor activity in combination with chemotherapy in a murine tumor model.

CKD-516 is a benzophenone analog in which the B ring is modified by replacement with a carbonyl group. The study assessed CKD-516 as a vascular disrupting agent or anti-cancer drug.
To assess the effect of S516 on vascularization, we analyzed the effect on human umbilical vein endothelial cells (HUVECs). To determine the inhibition of cell proliferation of S516, we used H460 lung carcinoma cells. The alteration of microtubules was analyzed using immunoblot, RT-PCR and confocal imaging. To evaluate the anti-tumor effects of gemcitabine and/or CKD-516, H460 xenograft mice were treated with CKD-516 (2.5 mg/kg) and/or gemcitabine (40 mg/kg), and tumor growth was compared with vehicle-treated control. For histologic analysis, liver, spleen and tumor tissues from H460 xenograft mice were obtained 12 and 24 h after CKD-516 injection.
Cytoskeletal changes of HUVECs treated with 10 nM S516 were assessed by immunoblot and confocal imaging. S516 disrupted tubulin assembly and resulted in microtubule dysfunction, which induced cell cycle arrest (G2/M). S516 markedly enhanced the depolymerization of microtubules, perhaps due to the vascular disrupting properties of S516. Interestingly, S516 decreased the amount of total tubulin protein in HUVECs. Especially, S516 decreased mRNA expression α-tubulin (HUVECs only) and β-tubulin (HUVECs and H460 cells) at an early time point (4 h). Immunocytochemical analysis showed that S516 changed the cellular microtubule network and inhibited the formation of polymerized microtubules. Extensive central necrosis of tumors was evident by 12 h after treatment with CKD-516 (2.5 mg/kg, i.p.). In H460 xenografts, CKD-516 combined with gemcitabine significantly delayed tumor growth up to 57 % and 36 % as compared to control and gemcitabine alone, respectively.
CKD-516 is a novel agent with vascular disrupting properties and enhances anti-tumor activity in combination with chemotherapy.
AuthorsChang Hoon Moon, Seung Ju Lee, Ho Yong Lee, Le Thi Kim Dung, Wha Ja Cho, HeeJeong Cha, Jeong Woo Park, Young Joo Min
JournalInvestigational new drugs (Invest New Drugs) Vol. 32 Issue 3 Pg. 400-11 (Jun 2014) ISSN: 1573-0646 [Electronic] United States
PMID24202729 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Antineoplastic Agents
  • Benzophenones
  • N-(4-(3-(1H-1,2,4-triazol-1-yl)-4-(3,4,5-trimethoxybenzoyl)phenyl)thiazol-2-yl)-2-amino-3-methylbutanamide
  • Tubulin
  • Deoxycytidine
  • gemcitabine
  • Valine
  • Animals
  • Antineoplastic Agents (administration & dosage, pharmacology)
  • Antineoplastic Combined Chemotherapy Protocols (therapeutic use)
  • Benzophenones (administration & dosage, pharmacology)
  • Cell Cycle Checkpoints (drug effects)
  • Cell Line, Tumor
  • Cell Proliferation (drug effects)
  • Cell Survival (drug effects)
  • Cells, Cultured
  • Deoxycytidine (administration & dosage, analogs & derivatives)
  • Female
  • Human Umbilical Vein Endothelial Cells (drug effects, metabolism)
  • Humans
  • Mice, Mutant Strains
  • Microtubules (drug effects, metabolism)
  • Neoplasms (drug therapy, pathology)
  • Neovascularization, Pathologic (drug therapy)
  • Tubulin (metabolism)
  • Tumor Burden (drug effects)
  • Valine (administration & dosage, analogs & derivatives, pharmacology)
  • Xenograft Model Antitumor Assays

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