Dual targeting of tumour cells and host endothelial cells by novel microtubule-targeting agents, pyrrolo-1,5-benzoxazepines.
OBJECTIVE
Some members of a novel series of pyrrolo-1,5-benzoxazepines (PBOXs) are microtubule-targeting agents capable of inducing apoptosis in a variety of human cancerous cells, hence, they are currently being developed as potential anti-cancer agents. The purpose of this study was to first characterise the activities of a novel PBOX analogue, PBOX-16 and then investigate the anti-angiogenic potential of both PBOX-16 and its prototype PBOX-6.


METHODS
The effects of PBOX-6 and -16 on cancerous cells (chronic myeloid leukaemia K562 cells and ovarian carcinoma A2780 cells) and primary cultured human umbilical vein endothelial cells (HUVECs) were examined by assessing cell proliferation, microtubular organisation, DNA analysis of cell cycle progression and caspase-3/7 activity. Their anti-angiogenic properties were then investigated by examining their ability to interfere with HUVEC differentiation into capillary-like structures and vascular endothelial growth factor (VEGF)-stimulated HUVEC migration.


RESULTS
PBOX-6 and -16 inhibited proliferation of K562, A2780 and HUVEC cells in a concentration-dependent manner. PBOX-16, confirmed as a novel depolymerising agent, was approximately tenfold more potent than PBOX-6. Inhibition of cell proliferation was mediated by G(2)/M arrest followed by varying degrees of apoptosis depending on the cell type; endothelial cells underwent less apoptosis than either of the cancer cell lines. In addition to the antitumourigenic properties, we also describe a novel antiangiogenic function for PBOXs: treatment with PBOXs inhibited the spontaneous differentiation of HUVECs into capillary-like structures when grown on a basement membrane matrix preparation (Matrigel™) and also significantly reduced VEGF-stimulated HUVEC migration.


CONCLUSIONS
Dual targeting of both the tumour cells and the host endothelial cells by PBOX compounds might enhance the anti-cancer efficacy of these drugs.
Nathwani
Seema-Maria
SM
School of Biochemistry and Immunology, Trinity College, Dublin, Ireland. nathwans@tcd.ie
Butler
Stephen
S
Meegan
Mary J
MJ
Campiani
Giuseppe
G
Lawler
Mark
M
Williams
D Clive
DC
Zisterer
Daniela M
DM
D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D001552:Benzazepines / Q000737:chemistry / Q000494:pharmacology*; D002219:Carbamates / Q000737:chemistry / Q000494:pharmacology*; D053148:Caspase 3 / Q000378:metabolism; D053179:Caspase 7 / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects* / Q000502:physiology; D004789:Enzyme Activation; D006801:Humans; D008870:Microtubules / Q000187:drug effects / Q000648:ultrastructure; D010077:Oxazepines / Q000737:chemistry / Q000494:pharmacology*; D011758:Pyrroles / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014404:Tubulin / Q000378:metabolism; D014471:Umbilical Veins / Q000166:cytology
C550734:4-((N,N-dimethylcarbamoyl)oxy)-5-(naphth-1-yl)naphtho(2,3-b)pyrrolo(1,2-d)(1,4)oxazepine; D000970:Antineoplastic Agents; D001552:Benzazepines; D002219:Carbamates; D010077:Oxazepines; D011758:Pyrroles; D014404:Tubulin; D053148:Caspase 3; D053179:Caspase 7; C418868:PBOX-6