Taxanes with high potency inducing tubulin assembly overcome tumoural cell resistances

Abstract

We have found that four taxanes with chemical modifications at positions C10 and C13 were active against all types of taxane resistant cell lines, resistant by P-gp overexpression, by mutations in the β-tubulin binding site or by overexpression of the highly dynamic βIII-tubulin isotype. We have characterized the interaction of taxanes with high activity on chemotherapy resistant tumoural cells with microtubules, and also studied their cellular effects. The biochemical property enhanced in comparison with other taxanes is their potency at inducing tubulin assembly, despite the fact that their interactions with the microtubule binding sites (pore and luminal) are similar as studied by NMR and SAXS. A differential interaction with the S7-S9 loop (M-loop) is responsible for their enhanced assembly induction properties. The chemical changes in the structure also induce changes in the thermodynamic properties of the interaction, indicating a higher hydrophilicity and also explaining their properties on P-gp and βIII overexpressing cells and on mutant cells. The effect of the compounds on the microtubular network is different from those observed with the classical (docetaxel and paclitaxel) taxanes, inducing different bundling in cells with microtubules being very short, indicating a very fast nucleation effect and reflecting their high assembly induction power.

Quest for Efficacious Next-Generation Taxoid Anticancer Agents and Their Tumor-Targeted Delivery

“…28 Apparently, these three next-generation taxoids induced tubulin assembly with much higher potency than paclitaxel and docetaxel. Thus, it is indicative that not only the rate of assembly was greater but also a larger number of microtubules was formed.…”

“…28 As Table 3 indicates, the binding of these three next-generation taxoids is much less exothermic with a large decrease in the enthalpy of binding, but this decrease in the enthalpy of binding was compensated for by a substantial increase in the entropy of binding, which suggests significant differences in the binding mechanism.…”

“…27 General structures of these second- and third-generation taxoids, i.e., “next-generation taxoids”, developed in our laboratory are shown in Figure 3. It is worth mentioning that these next-generation taxoids can overcome not only MDR by overexpression of Pgp 22 but also other taxane-resistance mechanisms such as the resistance caused by overexpression of βIII-tubulin 28 and point mutations at the taxane binding site 22 in microtubules.…”

“…28 As Table 2 shows, the binding of 26 is ca. 10 times stronger than paclitaxel and slightly better than 1 , while a third-generation taxoid, 20 , binds to microtubules 270–330 times stronger than paclitaxel.…”

A környezeti terhelések és patomechanizmusok kapcsolata

“…A tubulin szerkezetét érintő mutációk is rezisztencia kialakulásához vezetnek [43,44,45]. Jelentős rezisztencia típus még az MDR1 gén által kódolt P-gp fokozott expressziója következtében jelenik meg, ez a multidrog rezisztencia ismert formája, amely számos, eltérő kémiai szerkezetű, nagyobb molekulájú, természetes eredetű gyógyszerrel szembeni rezisztenciát jelent [46].…”