Publications by authors named "Rohith Kumar"

5 Publications

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A case of psychogenic Parkinsonism: Late age of onset should not be a barrier to make the diagnosis.

Aust N Z J Psychiatry 2018 11 8;52(11):1098. Epub 2018 Oct 8.

2 Academic Unit of Psychiatry and Addiction Medicine and College of Medicine, Biology, and Environment, ANU Medical School, Canberra, ACT, Australia.

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http://dx.doi.org/10.1177/0004867418804068DOI Listing
November 2018

ERK mediated upregulation of death receptor 5 overcomes the lack of p53 functionality in the diaminothiazole DAT1 induced apoptosis in colon cancer models: efficiency of DAT1 in Ras-Raf mutated cells.

Mol Cancer 2016 Mar 8;15:22. Epub 2016 Mar 8.

Cancer Research Program - 3, Rajiv Gandhi Centre for Biotechnology, Trivandrum, 695014, India.

Background: p53 is a tumour suppressor protein that plays a key role in many steps of apoptosis, and malfunctioning of this transcription factor leads to tumorigenesis. Prognosis of many tumours also depends upon the p53 status. Most of the clinically used anticancer compounds activate p53 dependent pathway of apoptosis and hence require p53 for their mechanism of action. Further, Ras/Raf/MEK/ERK axis is an important signaling pathway activated in many cancers. Dependence of diaminothiazoles, compounds that have gained importance recently due to their anticancer and anti angiogenic activities, were tested in cancer models with varying p53 or Ras/Raf mutational status.

Methods: In this study we have used p53 mutated and knock out colon cancer cells and xenograft tumours to study the role of p53 in apoptosis mediated by diaminothiazoles. Colon cancer cell lines with varying mutational status for Ras or Raf were also used. We have also examined the toxicity and in vivo efficacy of a lead diaminothiazole 4-Amino-5-benzoyl-2-(4-methoxy phenylamino)thiazole (DAT1) in colon cancer xenografts.

Results: We have found that DAT1 is active in both in vitro and in vivo models with nonfunctional p53. Earlier studies have shown that extrinsic pathway plays major role in DAT1 mediated apoptosis. In this study, we have found that DAT1 is causing p53 independent upregulation of the death receptor 5 by activating the Ras/Raf/MEK/ERK signaling pathway both in wild type and p53 suppressed colon cancer cells. These findings are also confirmed by the in vivo results. Further, DAT1 is more efficient to induce apoptosis in colon cancer cells with mutated Ras or Raf.

Conclusions: Minimal toxicity in both acute and subacute studies along with the in vitro and in vivo efficacy of DAT1 in cancers with both wild type and nonfunctional p53 place it as a highly beneficial candidate for cancer chemotherapy. Besides, efficiency in cancer cells with mutations in the Ras oncoprotein or its downstream kinase Raf raise interest in diaminothiazole class of compounds for further follow-up.
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http://dx.doi.org/10.1186/s12943-016-0505-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4782294PMC
March 2016

Reversible action of diaminothiazoles in cancer cells is implicated by the induction of a fast conformational change of tubulin and suppression of microtubule dynamics.

Mol Cancer Ther 2014 Jan 5;13(1):179-89. Epub 2013 Nov 5.

Corresponding Author: Suparna Sengupta, Division of Cancer Research, Rajiv Gandhi Centre for Biotechnology, Thiruvananthapuram 695014, India.

Diaminothiazoles are novel cytotoxic compounds that have shown efficacy toward different cancer cell lines. They show potent antimitotic and antiangiogenic activity upon binding to the colchicine-binding site of tubulin. However, the mechanism of action of diaminothiazoles at the molecular level is not known. Here, we show a reversible binding to tubulin with a fast conformational change that allows the lead diaminothiazole DAT1 [4-amino-5-benzoyl-2-(4-methoxy phenyl amino)thiazole] to cause a reversible mitotic block. DAT1 also suppresses microtubule dynamic instability at much lower concentration than its IC(50) value in cancer cells. Both growth and shortening events were reduced by DAT1 in a concentration-dependent way. Colchicine, the long-studied tubulin-binding drug, has previously failed in the treatment of cancer due to its toxicity, even though it generates a strong apoptotic response. The toxicity is attributable to its slow removal from the cell due to irreversible tubulin binding caused by a slow conformational change. DAT1 binds to tubulin at an optimal pH lower than colchicine. Tubulin conformational studies showed that the binding environments of DAT1 and colchicine are different. Molecular dynamic simulations showed a difference in the number of H-bonding interactions that accounts for the different pH optima. This study gives an insight of the action of compounds targeting tubulin's colchicine-binding site, as many such compounds have entered into clinical trials recently.
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http://dx.doi.org/10.1158/1535-7163.MCT-13-0479DOI Listing
January 2014

Fodrin in centrosomes: implication of a role of fodrin in the transport of gamma-tubulin complex in brain.

PLoS One 2013 1;8(10):e76613. Epub 2013 Oct 1.

Cancer Research Programme III, Rajiv Gandhi Centre for Biotechnology, Thiruvanantha-puram, Kerala, India.

Gamma-tubulin is the major protein involved in the nucleation of microtubules from centrosomes in eukaryotic cells. It is present in both cytoplasm and centrosome. However, before centrosome maturation prior to mitosis, gamma-tubulin concentration increases dramatically in the centrosome, the mechanism of which is not known. Earlier it was reported that cytoplasmic gamma-tubulin complex isolated from goat brain contains non-erythroid spectrin/fodrin. The major role of erythroid spectrin is to help in the membrane organisation and integrity. However, fodrin or non-erythroid spectrin has a distinct pattern of localisation in brain cells and evidently some special functions over its erythroid counterpart. In this study, we show that fodrin and γ-tubulin are present together in both the cytoplasm and centrosomes in all brain cells except differentiated neurons and astrocytes. Immunoprecipitation studies in purified centrosomes from brain tissue and brain cell lines confirm that fodrin and γ-tubulin interact with each other in centrosomes. Fodrin dissociates from centrosome just after the onset of mitosis, when the concentration of γ-tubulin attains a maximum at centrosomes. Further it is observed that the interaction between fodrin and γ-tubulin in the centrosome is dependent on actin as depolymerisation of microfilaments stops fodrin localization. Image analysis revealed that γ-tubulin concentration also decreased drastically in the centrosome under this condition. This indicates towards a role of fodrin as a regulatory transporter of γ-tubulin to the centrosomes for normal progression of mitosis.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0076613PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3788121PMC
April 2014

Vaidyamadham cheriya narayanan namboodiri.

J Ayurveda Integr Med 2010 Apr;1(2):136-8

Swami Vivekananda Yoga Anusandhana Samsthana, Bangalore, India.

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http://dx.doi.org/10.4103/0975-9476.65093DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3151383PMC
April 2010
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