scispace - formally typeset
Search or ask a question
Author

Gurmit Singh

Bio: Gurmit Singh is an academic researcher from McMaster University. The author has contributed to research in topics: Bone metastasis & Cancer cell. The author has an hindex of 54, co-authored 270 publications receiving 8565 citations. Previous affiliations of Gurmit Singh include McMaster University Medical Centre & Shiv Nadar University.


Papers
More filters
Journal ArticleDOI
TL;DR: The results suggest that metformin can be a clinically useful adjunct to radiotherapy in NSCLC and mediate their action through an ATM–AMPK-dependent pathway.
Abstract: Metformin inhibits growth and enhances radiation response of non-small cell lung cancer (NSCLC) through ATM and AMPK

240 citations

Journal ArticleDOI
TL;DR: This study shows that mitochondria in liver, kidney, heart, and brain of the mouse have a distinct mitochondrial density and demonstrates that the mtDNA copy number per mitochondrion is organ‐specific.
Abstract: This study shows that mitochondria in liver, kidney, heart, and brain of the mouse have a distinct mitochondrial density. It also demonstrates that the mtDNA copy number per mitochondrion is organ-specific. A reliable method of determining mitochondrial density per organ is by stereological analysis of tissue sections while mtDNA quantitation is by the use of radiolabelled mtDNA probe. This is the first study in which a comprehensive examination of mitochondrial density and quantitation of mitochondrial genomes in mouse organs have been done. In summary the variability is not only in mitochondrial density but also in genomic copy number in mitochondria of various tissues.

222 citations

Journal ArticleDOI
TL;DR: A direct competitive enzyme-linked immunosorbent assay (ELISA) was developed to detect a broad range of (fluoro)quinolones in various matrices and showed good detection capabilities for sarafloxacin and nalidixic acid.
Abstract: A direct competitive enzyme-linked immunosorbent assay (ELISA) was developed to detect a broad range of (fluoro)quinolones in various matrices. In the optimized generic test, anti-sarafloxacin antibodies in combination with norfloxacin conjugate showed 50% binding inhibition at 0.21 ng mL-1 for sarafloxacin in buffer. Screening for this class of antibiotics is accomplished using a simple, rapid extraction carried out with a 1:1 mixture of methanol and phosphate-buffered saline adjusted to pH 7.4. This common extraction was able to detect 15 (fluoro)quinolone residues such as sarafloxacin, norfloxacin, difloxacin, ciprofloxacin, pefloxacin, ofloxacin, cinoxacin, danofloxacin, enrofloxacin, marbofloxacin, lomefloxacin, enoxacin, flumequine, oxolinic acid, and nalidixic acid in pig kidney, poultry muscle, egg, fish, and shrimp. The assay's detection capabilities (CCβ) for most of these compounds were <10 μg kg-1 except for the sarafloxacin-, oxolinic acid-, flumequine-, and cinoxacin-spiked matrices, the est...

201 citations

Journal ArticleDOI
TL;DR: Evidence is provided that IR activates AMPK in human cancer cells in an LKB1-independent manner, leading to induction of p21(waf/cip) and regulation of the cell cycle and survival.
Abstract: Purpose Adenosine monophosphate (AMP)–activated kinase (AMPK) is a molecular energy sensor regulated by the tumor suppressor LKB1. Starvation and growth factors activate AMPK through the DNA damage sensor ataxia-telangiectasia mutated (ATM). We explored the regulation of AMPK by ionizing radiation (IR) and its role as a target for radiosensitization of human cancer cells. Methods and Materials Lung, prostate, and breast cancer cells were treated with IR (2–8 Gy) after incubation with either ATM or AMPK inhibitors or the AMPK activator metformin. Then, cells were subjected to either lysis and immunoblotting, immunofluorescence microscopy, clonogenic survival assays, or cell cycle analysis. Results IR induced a robust phosphorylation and activation of AMPK in all tumor cells, independent of LKB1. IR activated AMPK first in the nucleus, and this extended later into cytoplasm. The ATM inhibitor KU-55933 blocked IR activation of AMPK. AMPK inhibition with Compound C or anti–AMPK α subunit small interfering RNA (siRNA) blocked IR induction of the cell cycle regulators p53 and p21 waf/cip as well as the IR-induced G2/M arrest. Compound C caused resistance to IR, increasing the surviving fraction after 2 Gy, but the anti-diabetic drug metformin enhanced IR activation of AMPK and lowered the surviving fraction after 2 Gy further. Conclusions We provide evidence that IR activates AMPK in human cancer cells in an LKB1-independent manner, leading to induction of p21 waf/cip and regulation of the cell cycle and survival. AMPK appears to (1) participate in an ATM–AMPK–p21 waf/cip pathway, (2) be involved in regulation of the IR-induced G2/M checkpoint, and (3) may be targeted by metformin to enhance IR responses.

198 citations

Journal ArticleDOI
TL;DR: Evidence is provided that the expression of xCT, the light chain subunit of system xc−, is regulated by NRF2 in representative human breast cancer cells, demonstrating the importance of the KEAP1/NRF2 pathway in balancing oxidative stress in Breast cancer cells through system x c−.
Abstract: Cancer cells adapt to high levels of oxidative stress in order to survive and proliferate by activating key transcription factors. One such master regulator, the redox sensitive transcription factor NF E2 Related Factor 2 (NRF2), controls the expression of cellular defense genes including those encoding intracellular redox-balancing proteins involved in glutathione (GSH) synthesis. Under basal conditions, Kelch-like ECH-associated protein 1 (KEAP1) targets NRF2 for ubiquitination. In response to oxidative stress, NRF2 dissociates from KEAP1, entering the nucleus and binding to the antioxidant response element (ARE) in the promoter of its target genes. Elevated reactive oxygen species (ROS) production may deplete GSH levels within cancer cells. System xc−, an antiporter that exports glutamate while importing cystine to be converted into cysteine for GSH synthesis, is upregulated in cancer cells in response to oxidative stress. Here, we provided evidence that the expression of xCT, the light chain subunit of system xc−, is regulated by NRF2 in representative human breast cancer cells. Hydrogen peroxide (H2O2) treatment increased nuclear translocation of NRF2, also increasing levels of xCT mRNA and protein and extracellular glutamate release. Overexpression of NRF2 up-regulated the activity of the xCT promoter, which contains a proximal ARE. In contrast, overexpression of KEAP1 repressed promoter activity and decreased xCT protein levels, while siRNA knockdown of KEAP1 up-regulated xCT protein levels and transporter activity. These results demonstrate the importance of the KEAP1/NRF2 pathway in balancing oxidative stress in breast cancer cells through system xc−. We have previously shown that xCT is upregulated in various cancer cell lines under oxidative stress. In the current investigation, we focused on MCF-7 cells as a model for mechanistic studies.

181 citations


Cited by
More filters
01 Aug 2000
TL;DR: Assessment of medical technology in the context of commercialization with Bioentrepreneur course, which addresses many issues unique to biomedical products.
Abstract: BIOE 402. Medical Technology Assessment. 2 or 3 hours. Bioentrepreneur course. Assessment of medical technology in the context of commercialization. Objectives, competition, market share, funding, pricing, manufacturing, growth, and intellectual property; many issues unique to biomedical products. Course Information: 2 undergraduate hours. 3 graduate hours. Prerequisite(s): Junior standing or above and consent of the instructor.

4,833 citations

Book
01 May 1988
TL;DR: A comprehensive review of mechanisms of subcellular and tumor localization of photosensitizing agents, as well as of molecular, cellular, and tumor responses associated with photodynamic therapy, are discussed.
Abstract: Photodynamic therapy involves administration of a tumor-localizing photosensitizing agent, which may require metabolic synthesis (i.e., a prodrug), followed by activation of the agent by light of a specific wavelength. This therapy results in a sequence of photochemical and photobiologic processes that cause irreversible photodamage to tumor tissues. Results from preclinical and clinical studies conducted worldwide over a 25-year period have established photodynamic therapy as a useful treatment approach for some cancers. Since 1993, regulatory approval for photodynamic therapy involving use of a partially purified, commercially available hematoporphyrin derivative compound (Photofrin) in patients with early and advanced stage cancer of the lung, digestive tract, and genitourinary tract has been obtained in Canada, The Netherlands, France, Germany, Japan, and the United States. We have attempted to conduct and present a comprehensive review of this rapidly expanding field. Mechanisms of subcellular and tumor localization of photosensitizing agents, as well as of molecular, cellular, and tumor responses associated with photodynamic therapy, are discussed. Technical issues regarding light dosimetry are also considered.

4,580 citations

Journal ArticleDOI
TL;DR: The photodynamic therapy (PDT) is a clinically approved, minimally invasive therapeutic procedure that can exert a selective cytotoxic activity toward malignant cells as discussed by the authors, which can prolong survival in patients with inoperable cancers and significantly improve quality of life.
Abstract: Photodynamic therapy (PDT) is a clinically approved, minimally invasive therapeutic procedure that can exert a selective cytotoxic activity toward malignant cells. The procedure involves administration of a photosensitizing agent followed by irradiation at a wavelength corresponding to an absorbance band of the sensitizer. In the presence of oxygen, a series of events lead to direct tumor cell death, damage to the microvasculature, and induction of a local inflammatory reaction. Clinical studies revealed that PDT can be curative, particularly in early stage tumors. It can prolong survival in patients with inoperable cancers and significantly improve quality of life. Minimal normal tissue toxicity, negligible systemic effects, greatly reduced long-term morbidity, lack of intrinsic or acquired resistance mechanisms, and excellent cosmetic as well as organ function-sparing effects of this treatment make it a valuable therapeutic option for combination treatments. With a number of recent technological improvements, PDT has the potential to become integrated into the mainstream of cancer treatment. CA Cancer J Clin 2011;61:250-281. V C

3,770 citations

Journal ArticleDOI
TL;DR: This Perspective has organized known cancer-associated metabolic changes into six hallmarks: deregulated uptake of glucose and amino acids, use of opportunistic modes of nutrient acquisition, useof glycolysis/TCA cycle intermediates for biosynthesis and NADPH production, increased demand for nitrogen, alterations in metabolite-driven gene regulation, and metabolic interactions with the microenvironment.

3,565 citations

Journal ArticleDOI
TL;DR: AMP-activated protein kinase conserves ATP levels through the regulation of processes other than metabolism, such as the cell cycle and neuronal membrane excitability.
Abstract: AMP-activated protein kinase (AMPK) is a crucial cellular energy sensor. Once activated by falling energy status, it promotes ATP production by increasing the activity or expression of proteins involved in catabolism while conserving ATP by switching off biosynthetic pathways. AMPK also regulates metabolic energy balance at the whole-body level. For example, it mediates the effects of agents acting on the hypothalamus that promote feeding and entrains circadian rhythms of metabolism and feeding behaviour. Finally, recent studies reveal that AMPK conserves ATP levels through the regulation of processes other than metabolism, such as the cell cycle and neuronal membrane excitability.

3,465 citations