Taccalonolides: A Novel Class of Microtubule-Stabilizing Anticancer Agents

Abstract

Microtubule stabilizing agents, such as paclitaxel, docetaxel, and cabazitaxel have been among the most used chemotherapeutic agents in the last decades for the treatment of a wide range of cancers in the clinic. One of the concerns that limit their use in clinical practice is their intrinsic and acquired drug resistance, which is common to most anti-cancer chemotherapeutics. Taccalonolides are a new class of microtubule stabilizers isolated from the roots of a few species in the genus of Tacca. In early studies, taccalonolides demonstrated different effects on interphase and mitotic microtubules from those of paclitaxel and laulimalide suggesting a unique mechanism of action. This prompts the exploration of new taccalonolides with various functionalities through the identification of minor constituents of natural origin and semi-synthesis. The experiments on the new highly potent taccalonolides indicated that taccalonolides possessed a unique mechanism of covalently binding to the microtubule. An X-ray diffraction analysis of a crystal of taccalonolides AJ binding to tubulin indicated that the covalent binding site is at β-tubulin D226. Taccalonolides circumvent all three mechanisms of taxane drug resistance both in vitro and in vivo. To improve the activity, the structure modification through semi-synthesis was conducted and the structure-activity relationships (SARs) was analyzed based on natural and semi-synthetical taccalonolides. The C22-C23 epoxide can significantly increase the antiproliferation potency of taccalonolides due to the covalent link of C22 and the carboxylic group of D226. Great progress has been seen in the last few years in the understanding of the mechanism of this class of microtube-stabilizing agents. This review summarizes the structure diversity, structure-activity relationships (SARs), mechanism of action, and in vivo activities of taccalonolides.

Antitumor Profile of Carbon-Bridged Steroids (CBS) and Triterpenoids

“…A 3D graph of the predicted antitumor activities is shown in Figure 25. The data we obtained using PASS are supported by the data just published by Peng and colleagues, which shows a wide range of biological activities of taccalonolides [271]. The withanolide glucoside named trichoside B (197) is of type A-nor-sterols, and was isolated from the methanolic extract of aerial parts of Tricholepis eburnea, which is native to Afghanistan, compound ( 206) is a testosterone derivative dimer, and the steroid ( 214) contains a cyclobutane ring in ring A of the steroid.…”

“…A 3D graph of the predicted antitumor activities is shown in Figure 25. The data we obtained using PASS are supported by the data just published by Peng and colleagues, which shows a wide range of biological activities of taccalonolides [271]. (271).…”

“…Their pharmacological profile is presented in Tables 16 and 17. Carbon-bridged steroids, called taccalonolides (265)(266)(267)(268)(269)(270)(271), are a class of microtubulestabilizing agents that exhibit selective cancer-fighting properties [233]. Tacca species are known to contain highly oxygenated ixocarpalactone-type steroids, with an additional ring formed by a carbon-carbon bond between C-16 and C-24, taccalonolide A being the first example of these compounds [120].…”

“…Figure25. The 3D graph shows the predicted and calculated pharmacological activities of taccalonolide Q(271). Taccalonolide Q, similar to other taccalonolides, is a class of highly acetoxylated pentacyclic steroids containing 28 carbons, known microtubule stabilizing cytotoxic agents isolated from the genus Tacca that have selective anti-cancer properties.…”

An HDAC9-associated immune-related signature predicts bladder cancer prognosis

“…The six chemotherapy drugs included in the study affected the metabolic process to varying degrees. Among the chemotherapeutic drugs with differences between the two risk groups, cisplatin could induce cell cycle G1/S arrest [ 89 ], docetaxel promoted the formation of tubulin structures [ 90 ], methotrexate prohibited folic acid metabolism [ 91 ] and gemcitabine inhibited DNA replication [ 92 ]. The GO results indicated G1/S cell cycle arrest (GOBP_NEGATIVE_REGULATION_OF_CELL_CYCLE_G1_S_PHASE_TRANSITION), tubulin structure synthesis (GO_TUBULIN_BINDING), folic acid metabolism process (GO_FOLIC_ACID_METABOLIC_PROCESS), and the DNA replication (GO_POSITIVE_REGULATION_OF_DNA_REPLICATION) related biological functions were enriched in the high-risk group, implying that chemotherapy effectiveness depended on whether the drug mechanism conflicted with the metabolic changes of the patients themselves.…”