Meet the Expert RGCB Blog

Issue 4

30/09/2015

Drug resistance: Through a magnifying glass

Acquired drug resistance is a major hurdle in cancer chemotherapy. Mechanistically anticancer drug resistance is intricate in nature. It has been observed that chemotherapy using molecules above a certain size suffer from drug efflux as they are generally the substrates of transmembrane pumps. Small molecules often escape the pumps but also elicit resistance, the mechanism of which is not much known. Identifying agents that are sensitive to drug resistant tumors and specifically dissecting small molecule versus large molecule resistance mechanisms is important so that proper combinations can be planned in the clinics.

In this issue: Drug resistance: Sengupta et al delved into the factors differentiating broad spectrum from specific resistance. The findings were published in the August issue of Carcinogenesis as Diaminothiazoles

Evade Multidrug Resistance in Cancer Cells and Xenograft Tumour Models and Develop Transient Specific Resistance: Understanding the Basis of Broad-Spectrum vs Specific Resistance. RGCB Blog recognizes the efforts of her team.

Through a magnifying glass

Suparna Sengupta PhD Diaminothiazoles In Drug Resistance Bumps in the road Further plans The Team

Suparna Sengupta PhD Suparna Sengupta holds a doctoral degree in Biochemistry from Bose

Institute, Calcutta. After gaining postdoctoral research experience from University of Kansas, USA, she joined as Scientist C in RGCB in 2000. Currently, she is Scientist E II, running Cancer Research Program-3 of RGCB with her team of research fellows and graduate students. She holds three patents in synthetic diaminoketothiazoles.

Reference

Diaminothiazoles Our laboratory is working intensively with small sized, synthetic, antimitotic agents with potential anticancer activities. We have got encouraging results with small molecules in the diaminothiazole class as possible candidates for future drug development. Synthetic derivatives of dendrodoine (derived from marine tunicate Dendrodoa grossularia), show amazing multispectrum actions and applications not only limited to cancer, but also cardiovascular diseases, diabetes and neurodegenerative diseases like Alzheimer’s disease. As anticancer agents these compounds show the merit of suppressing the microtubule dynamics leading to cell cycle arrest, reversible binding to tubulin which accounts for their low toxicity and triggering apoptosis which is mostly executed by a death receptor mediated pathway. The antiangiogenic potential of these compounds is also a valuable attribute for their clinical utility.

“Diaminothiazoles are a novel class of antimitotic and antiangiogenic compounds. They are capable of inducing apoptosis by both intrinsic and extrinsic pathways and in cells where the mitochondrial pathway is blocked. Lead diaminothiazole DAT1 has been shown to bind to the classical colchicine site of tubulin and depolymerize microtubules reversibly.”

In Drug Resistance We have used diaminothiazoles and paclitaxel (taxol) as gauge compounds both in vitro and in vivo against multidrug resistant cancer models generated in the laboratory. We have reported that the resistance developed in cancer cells against large sized antimitotic agents is broad-spectrum as well as multifactorial including transmembrane pumps. On the contrary, resistance developed against small molecules is transient in nature, mostly contributed by target specific modulations and variations in apoptotic proteins. These findings were further validated and confirmed in xenograft tumor models in SCID mice. Importantly, diaminothiazoles showed significant in vivo activity in human multidrug resistant cancer xenograft tumor models. This work paves the way for small sized compounds in the diaminothiazole class for the treatment of drug refractory tumors which are resistant to the conventional chemotherapeutic agents. Also, our work facilitated in understanding some of the uncharted small molecule resistance mechanisms, for which at present only limited information is available in the literature.

Bumps in the road Developing drug resistant colon and breast cancer cells was a time consuming process. We had employed a step-wise selection process to cancer cells in the increasing drug concentration, to obtain drug resistant lines which needed a good amount of patience and a time span ranging from about 8 to 15 months. Further, we faced administrative and technical problems to receive adequate cancer tissues from patients and thus efficacy of these compounds on primary human cancer cells are yet to be tested.

The Team This work is a result of intra and inter-institutional collaborations. The lead author of the work, SmretiVasudevan, is one of the most sincere, methodical and perfectionist students I have ever seen. She has raised the resistant cell lines with much patience over fifteen months and prevented them from contamination and other hurdles. The lion share of bench work was done by her. Sannu Thomas initially started the project with some commercially available cell lines. Professor Rajasekharan of the Department of Chemistry, University of Kerala and two of his students have contributed a lot by synthesizing the compounds used for this work. K.C.Sivakumar of the Distributed Information Sub Centre, Rajiv Gandhi Centre for Biotechnology, has helped in the modeling and docking of different diaminothiazoles and other antimitotic drugs to multidrug resistant protein (MDR1) and tubulin isotypes. We were also timely helped by other labs in RGCB as and when needs arose.

Ref: Diaminothiazoles Evade Multidrug Resistance in Cancer Cells and Xenograft Tumour Models and Develop Transient Specific Resistance: Understanding the Basis of Broad-Spectrum vs Specific Resistance

Further systematic analysis plans for future “We are further interested to study the epigenetic switches regulating antimitotic drug resistance. A thorough mechanistic study would help in better understanding of the activity of these drugs. “ “Pharmacokinetic profiling of diaminothiazoles is essential. Indeed, this compelling class of compounds, some of which can inhibit cancer cells in nanomolar concentrations, deserves to be tested in further pre-clinical and eventually to clinical settings.”