The Vascular Targeting Agent Combretastatin-A4 and a Novelcis-Restricted β-Lactam Analogue, CA-432, Induce Apoptosis in Human Chronic Myeloid Leukemia Cells and Ex Vivo Patient Samples Including Those Displaying Multidrug Resistance

Abstract

Combretastatin-A4

Novel cis-restricted β-lactam combretastatin A-4 analogues display anti-vascular and anti-metastatic properties in vitro

“…We determined that both analogues potently inhibited HUVEC proliferation with IC 50 values of 24.9 nM and 4 nM for CA-104 and CA-432, respectively. These values were either similar or lower than those we previously observed in tumour cells such as breast carcinoma MCF-7 and MDA-MB-231 cells, promyelocytic leukaemia HL60 cells, chronic myeloid leukaemia K562 cells and ovarian carcinoma A2780 cells, where IC 50 values ranged between 17 and 60 nM for CA-104 and 7.5 and 28 nM for CA-432 (18)(19)(20). The magnitude of response obtained with CA-432 was similar to those reported for CA-4 and CA-4P which also demonstrated anti-proliferative effects on endothelial cells at lower concentrations than tumour cells (7,37).…”

“…Tubulin depolymerisation and G 2 M arrest are typical responses observed in tumour cells after exposure to the β-lactam analogues (19,20) and also parallels the effects observed with CA-4/CA-4P in endothelial cells (43). Studies suggest that the type of cell death culminating from CA-4(P)-induced G 2 M arrest varies depending on the conditions and the type of cell.…”

“…Replacement of the ethylene bridge of CA-4 with a β-lactam (2-azetidinone) ring provided a rigid scaffold that prevented cis-trans isomerisation and maintained a similar spatial arrangement between the two phenol rings as the cis-conformation of CA-4 (18). We have already established that some of these compounds displayed potent anti-proliferative activity in several cancer cell lines and ex vivo patient samples, including those displaying multidrug resistance (18)(19)(20)(21). However, the anti-vascular and anti-metastatic properties of these cisrestricted analogues remained to be elucidated.…”

“…Molecular docking studies indicated that representative compounds were capable of interacting with tubulin with similar positioning to CA-4. Several compounds inhibited tubulin polymerisation in vitro and demonstrated potent anti-mitotic potential in a selection of tumour cell lines derived of diverse origin including leukaemia, breast, non-small cell lung, colon, CNS, melanoma, ovarian, cervical, renal and prostate cancers (18)(19)(20)(21).…”

“…Molecular docking studies supported the notion that CA-432 was not a substrate for P-glycoprotein. Furthermore, CA-432 induced apoptosis in ex vivo samples from chronic myeloid leukaemia (CML) patients including those displaying resistance to imatinib mesylate, the frontline treatment for CML (20).…”