ABSTRACT
Acquired drug resistance poses a challenge in cancer therapy. Drug efflux is the most common mechanism of resistance displayed by hydrophobic drugs beyond a certain size. However, target specific changes and imbalance between the pro- and anti-apoptotic proteins are also found quite often in many tumours. A number of small antimitotic agents show high potential for multidrug resistant tumours, mainly because they are able to evade the efflux pumps. However, these compounds are also likely to suffer from resistance upon prolonged treatment. Thus, it is important to find out agents that are sensitive to resistant tumours and to know the resistance mechanisms against small molecules so that proper combinations can be planned. In this report, we have studied the efficiency of diaminothiazoles, a novel class of tubulin targeting potential anticancer compounds of small size, in multidrug resistant cancer. Studies in model cell lines raised against taxol and the lead diaminothiazole, DAT1 [4-amino-5-benzoyl-2-(4-methoxy phenyl amino) thiazole], and the xenograft tumours derived from them, show that diaminothiazoles are highly promising against multidrug resistant cancers. They were able to overcome the expression of efflux protein MDR1 and certain tubulin isotypes, could sensitize improper apoptotic machinery and ablated checkpoint proteins Bub1 and Mad2. Further, we have found that the resistance against microtubule binding compounds with higher size is broad-spectrum and emerges due to multiple factors including overexpression of transmembrane pumps. However, resistance against small molecules is transient, specific and is contributed by target specific changes and variations in apoptotic factors.
Subject(s)
Antineoplastic Agents/pharmacology , Drug Resistance, Neoplasm/drug effects , Thiazoles/pharmacology , ATP Binding Cassette Transporter, Subfamily B/metabolism , ATP Binding Cassette Transporter, Subfamily B, Member 1/chemistry , ATP Binding Cassette Transporter, Subfamily B, Member 1/metabolism , Animals , Antineoplastic Agents/chemistry , Cell Line, Tumor/drug effects , Drug Resistance, Multiple/drug effects , Female , Humans , Male , Mice, SCID , Molecular Docking Simulation , Paclitaxel/pharmacology , Thiazoles/chemistry , Tubulin/chemistry , Tubulin/metabolism , Xenograft Model Antitumor AssaysABSTRACT
Microtubules and their component protein, tubulin, constitute a popular target for the treatment of cancer. Many drugs that are presently used in clinics or in clinical trials and drugs that show promise as anticancer drugs bind to tubulin and microtubules. There are three conventional binding sites on beta-tubulin where many of these drugs bind. The binding properties, conformational changes upon binding, association constants and thermodynamic parameters for the drug-tubulin interaction on these three sites are discussed. The antiproliferative activities of these drugs and the possible correlation with the binding properties are also described.