Abstract
The cis-stilbene, combretastatin A4 (CA4), is a potent microtubule targeting and vascular damaging agent. Despite promising results at the pre-clinical level and extensive clinical evaluation, CA4 has yet to be approved for therapeutic use. One impediment to the development of CA4 is an inherent conformational instability about the ethylene linker, which joins two aromatic rings. We have previously published preliminary data regarding structurally simplified biphenyl derivatives of CA4, lacking an ethylene linker, which retain anti-proliferative and pro-apoptotic activity, albeit at higher doses. Our current study provides a more comprehensive evaluation regarding the anti-proliferative and pro-apoptotic properties of biphenyl CA4 derivatives in both 2D and 3D cancerous and non-cancerous cell models. Computational analysis has revealed that cytotoxicity of CA4 and biphenyl analogues correlates with predicted tubulin affinity. Additional mechanistic evaluation of the biphenyl derivatives found that their anti-cancer activity is dependent on prolonged mitotic arrest, in a similar manner to CA4. Lastly, we have shown that cancer cells deficient in the extrinsic pathway of apoptosis experience delayed cell death following treatment with CA4 or analogues. Biphenyl derivatives of CA4 represent structurally simplified analogues of CA4, which retain a similar mechanism of action. The biphenyl analogues warrant in vivo examination to evaluate their potential as vascular damaging agents.
Highlights
Combretastatin A4 (CA4; Fig 1) is a cis-stilbene that was first isolated from the South African bushwillow tree in 1989 [1]
The one cell line that was only minimally affected by treatment with CA4 was the HT-29 colorectal cancer cell line, which had been previously established as CA4-resistent [30]
We reported that CA4 and the two biphenyl analogues possessed anti-proliferative and pro
Summary
Combretastatin A4 (CA4; Fig 1) is a cis-stilbene that was first isolated from the South African bushwillow tree in 1989 [1]. CA4 and its related compound, colchicine (Fig 1), belong to a class of compounds referred to as colchicinoids. In the past several decades, CA4 has been found to be a potent microtubule targeting agent (MTA) and capable of drastically inhibiting cancer cell proliferation in vitro. In vivo studies have revealed that CA4 is a vascular disrupting agent (VDA), which is a classification that refers to compounds that can destroy newly formed vasculature, such as found in tumour environments [2, 3]. PLOS ONE | DOI:10.1371/journal.pone.0171806 March 2, 2017
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