Open AccessBPR0C261 is a novel orally active antitumor agent with antimitotic and anti‐angiogenic activities
Author(s) -
Hu ChihBo,
Chen ChingPing,
Yeh TengKuang,
Song JenShin,
Chang ChiYen,
Chuu JiunnJye,
Tung FeiFeng,
Ho PeiYin,
Chen TungWei,
Lin ChiHung,
Wang MinHsien,
Chang KaiYen,
Huang ChenLung,
Lin HengLiang,
Li WenTai,
Hwang DerRen,
Chern JyhHaur,
Hwang LingLing,
Chang JangYang,
Chao YuSheng,
Chen ChiungTong
Publication year - 2011
Publication title -
cancer science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.035
H-Index - 141
eISSN - 1349-7006
pISSN - 1347-9032
DOI - 10.1111/j.1349-7006.2010.01744.x
Subject(s) - pharmacology , in vivo , angiogenesis , cancer cell , clonogenic assay , cisplatin , cancer research , cytotoxic t cell , biology , cancer , chemistry , in vitro , biochemistry , chemotherapy , genetics , microbiology and biotechnology
BPR0C261 is a synthetic small molecule compound cytotoxic against human cancer cells and active prolonging the lifespan of leukemia mice. In the present study, we further investigated the mechanisms of its anticancer action and found that BPR0C261 inhibited microtubule polymerization through interacting with the colchicine binding sites on tubulins, disrupted microtubule arrangement and caused cell cycle arrest at G 2 /M phase in cancer cells. BPR0C261 also inhibited the clonogenic growths of cancer cells and showed cytotoxicity against human cervical cancer cells of multidrug‐resistant phenotype. In addition, BPR0C261 concentration‐dependently inhibited the proliferation and migration of HUVECs and disrupted the endothelial capillary‐like tube formations in HUVEC and rat aorta ring cultures. Given orally, BPR0C261 inhibited angiogenesis in s.c. implanted Matrigel plugs in mice. Notably, its IC 50 values against the endothelial cell growths were approximately 10‐fold lower than those against the cancer cells. It was found orally absorbable in mice and showed a good oral bioavailability (43%) in dogs. BPR0C261 permeated through the human intestinal Caco‐2 cell monolayer, suggesting oral availability in humans. Orally absorbed BPR0C261 distributed readily into the s.c. xenografted tumors in nude mice in which the tumor tissue levels of BPR0C261 were found oral dose‐dependent. BPR0C261 showed in vivo activities against human colorectal, gastric, and nasopharyngeal tumors in nude mice. Most interestingly, the combination of BPR0C261 plus cisplatin synergistically prolonged the lifespans of mice inoculated with murine leukemia cells. Thus, BPR0C261 is a novel orally active tubulin‐binding antitumor agent with antimitotic, apoptosis‐inducing, and vasculature disrupting activities. ( Cancer Sci 2011; 102: 182–191)