BPR0C261 is a novel orally active antitumor agent with antimitotic and anti‐angiogenic activities

Abstract

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 G2/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 IC50 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)

An Orally Bioavailable, Indole-3-glyoxylamide Based Series of Tubulin Polymerization Inhibitors Showing Tumor Growth Inhibition in a Mouse Xenograft Model of Head and Neck Cancer

“…This study builds on previous work by others which has already established a range of compounds of the indole-3-glyoxylamide class, such as 1 and 2 , as promising tubulin polymerization inhibitors. Other members of the class have been investigated preclinically, − including 88 – 91 (Figure ) arising from an SAR study published shortly after the disclosure of 1 , with both 90 and 91 reportedly demonstrating in vivo activity.…”

An Overview of Tubulin Inhibitors That Interact with the Colchicine Binding Site

“…N -Heterocyclic indolyl glyoxylamide BPR0C261 ( 84 ) is an analog of indibulin ( 17 ) and possesses in vitro/in vivo anticancer activities (80,81). BPR0C261 destabilizes microtubules and blocks cell cycle transition specifically at G2/M phase.…”

“…Moreover, apoptosis induction in the cancer cells is another underlying mechanism for the anticancer effects of BPR0C261. Colchicine binding assay indicated BPR0C261 at both 5 and 20 μM competitively binds to tubulin and strongly interferes with the colchicine binding to tubulin (80). In addition, BPR0C261 concentration-dependently inhibited the proliferation and migration of HUVECs with an IC 50 value of 1.6 nM and disrupted the endothelial capillary-like 2D tube formations of HUVEC.…”

Anticancer potential of magnolol for lung cancer treatment

“…The fact that the growth and spread of tumors is dependent on angiogenesis has led to investigation into the role of antiangiogenic agents in therapeutic strategies for thoracic tumors such as NSCLC or mesotheliomas. Hu et al reported that BPR0C261 is a novel orallyadministered active antitumor agent with antimitotic and antiangiogenic properties (Hu et al, 2011). In this study, we demonstrated that magnolol suppressed bFGF-induced angiogenesis in HUVECs.…”