Structurally simplified biphenyl combretastatin A4 derivatives retain in vitro anti-cancer activity dependent on mitotic arrest

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.

Discovery of novel quinoline-based analogues of combretastatin A-4 as tubulin polymerisation inhibitors with apoptosis inducing activity and potent anticancer effect

“…Activation of caspases initiates apoptosis, and in particular caspase-9 is considered an important effector caspase responsible for programmed cell death apoptosis activated by CA-4 61 , 65 , 66 . The amount of activated caspase-9 was examined in MCF-7 cells treated with 12c .…”

“…MCF-7 cells treated with 12c at 250 nM for 48 h decreased the expression level of the anti-apoptotic protein Bcl-2, and correspondingly up-regulated the expression of the pro-apoptotic protein Bax ( Figure 6(A,B)). Activation of caspases initiates apoptosis, and in particular caspase-9 is considered an important effector caspase responsible for programmed cell death apoptosis activated by CA-4 61,65,66 . The amount of activated caspase-9 was examined in MCF-7 cells treated with 12c.…”

Potent Quinoline-Containing Combretastatin A-4 Analogues: Design, Synthesis, Antiproliferative, and Anti-Tubulin Activity

“…Several literature reports document that CA-4 is vulnerable towards photoisomerization whereby it is converted to the inactive trans isomer during both storage and administration. The trans isomer is largely inactive as an anti-cancer agent with minimal anti-tubulin and cytotoxic activity [ 16 , 17 ]. Accordingly, rigidification of the alkenyl double bond has overcome this undesirable isomerization towards the less active trans isomer of CA-4.…”

Deciphering the origins of molecular toxicity of combretastatin A4 and its glycoconjugates: interactions with major drug transporters and their safety profiles in vitro and in vivo

“…CA4 has been found to have potent cytotoxic activity in colorectal cancer cell lines, such as HT-29 cells. 24 In this study, the cytotoxicity of CA4 and its sugar conjugates was first evaluated in HT-29 cells. As illustrated in Fig.…”