Publications by authors named "Suraj Radhamani"

8 Publications

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Correction: Combined poly-ADP ribose polymerase and ataxia-telangiectasia mutated/Rad3-related inhibition targets ataxia-telangiectasia mutated-deficient lung cancer cells.

Br J Cancer 2020 Jun;122(12):1872

Departments of Biochemistry and Molecular Biology, Robson DNA Science Centre and Charbonneau Cancer Institute, Cumming School of Medicine, University of Calgary, 3330 Hospital Drive NW, Calgary, Alberta, T2N 1N4, Canada.

This Article was originally published under Nature Research's License to Publish, but has now been made available under a CC BY 4.0 license. This has now been corrected in both the PDF and HTML versions of the Article.
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http://dx.doi.org/10.1038/s41416-020-0841-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7283263PMC
June 2020

Nocodazole-Induced Expression and Phosphorylation of Anillin and Other Mitotic Proteins Are Decreased in DNA-Dependent Protein Kinase Catalytic Subunit-Deficient Cells and Rescued by Inhibition of the Anaphase-Promoting Complex/Cyclosome with proTAME but Not Apcin.

Mol Cell Biol 2020 06 15;40(13). Epub 2020 Jun 15.

Department of Biochemistry and Molecular Biology and Robson DNA Science Centre, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada

The DNA-dependent protein kinase catalytic subunit (DNA-PKcs) has well-established roles in DNA double-strand break repair, and recently, nonrepair functions have also been reported. To better understand its cellular functions, we deleted DNA-PKcs from HeLa and A549 cells using CRISPR/Cas9. The resulting cells were radiation sensitive, had reduced expression of ataxia-telangiectasia mutated (ATM), and exhibited multiple mitotic defects. Mechanistically, nocodazole-induced upregulation of cyclin B1, anillin, and securin was decreased in DNA-PKcs-deficient cells, as were phosphorylation of Aurora A on threonine 288, phosphorylation of Polo-like kinase 1 (PLK1) on threonine 210, and phosphorylation of targeting protein for Klp2 (TPX2) on serine 121. Moreover, reduced nocodazole-induced expression of anillin, securin, and cyclin B1 and phosphorylation of PLK1, Aurora A, and TPX2 were rescued by inhibition of the anaphase-promoting complex/cyclosome (APC/C) by proTAME, which prevents binding of the APC/C-activating proteins Cdc20 and Cdh1 to the APC/C. Altogether, our studies suggest that loss of DNA-PKcs prevents inactivation of the APC/C in nocodazole-treated cells.
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http://dx.doi.org/10.1128/MCB.00191-19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7296215PMC
June 2020

ATM-Deficient Cancers Provide New Opportunities for Precision Oncology.

Cancers (Basel) 2020 Mar 14;12(3). Epub 2020 Mar 14.

Department of Biochemistry and Molecular Biology, Robson DNA Science Centre, Charbonneau Cancer Institute, Cumming School of Medicine, University of Calgary, 3330 Hospital Drive NW, Calgary, AB T2N 1N4, Canada.

Poly-ADP ribose polymerase (PARP) inhibitors are currently used in the treatment of several cancers carrying mutations in the breast and ovarian cancer susceptibility genes and , with many more potential applications under study and in clinical trials. Here, we discuss the potential for extending PARP inhibitor therapies to tumours with deficiencies in the DNA damage-activated protein kinase, Ataxia-Telangiectasia Mutated (ATM). We highlight our recent findings that PARP inhibition alone is cytostatic but not cytotoxic in ATM-deficient cancer cells and that the combination of a PARP inhibitor with an ATR (ATM, Rad3-related) inhibitor is required to induce cell death.
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http://dx.doi.org/10.3390/cancers12030687DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7140103PMC
March 2020

Combined poly-ADP ribose polymerase and ataxia-telangiectasia mutated/Rad3-related inhibition targets ataxia-telangiectasia mutated-deficient lung cancer cells.

Br J Cancer 2019 10 4;121(7):600-610. Epub 2019 Sep 4.

Departments of Biochemistry and Molecular Biology, Robson DNA Science Centre and Charbonneau Cancer Institute, Cumming School of Medicine, University of Calgary, 3330 Hospital Drive NW, Calgary, Alberta, T2N 1N4, Canada.

Background: Up to 40% of lung adenocarcinoma have been reported to lack ataxia-telangiectasia mutated (ATM) protein expression. We asked whether ATM-deficient lung cancer cell lines are sensitive to poly-ADP ribose polymerase (PARP) inhibitors and determined the mechanism of action of olaparib in ATM-deficient A549 cells.

Methods: We analysed drug sensitivity data for olaparib and talazoparib in lung adenocarcinoma cell lines from the Genomics of Drug Sensitivity in Cancer (GDSC) project. We deleted ATM from A549 lung adenocarcinoma cells using CRISPR/Cas9 and determined the effects of olaparib and the ATM/Rad3-related (ATR) inhibitor VE-821 on cell viability.

Results: IC values for both olaparib and talazoparib positively correlated with ATM mRNA levels and gene amplification status in lung adenocarcinoma cell lines. ATM mutation was associated with a significant decrease in the IC for olaparib while a similar trend was observed for talazoparib. A549 cells with deletion of ATM were sensitive to ionising radiation and olaparib. Olaparib induced phosphorylation of DNA damage markers and reversible G2 arrest in ATM-deficient cells, while the combination of olaparib and VE-821 induced cell death.

Conclusions: Patients with tumours characterised by ATM-deficiency may benefit from treatment with a PARP inhibitor in combination with an ATR inhibitor.
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http://dx.doi.org/10.1038/s41416-019-0565-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6889280PMC
October 2019

Role of a novel benzoxazine derivative in the chemosensitization of colon cancer.

Apoptosis 2017 08;22(8):988-1000

School of Pharmacy and Applied Science, Latrobe Institute of Molecular Sciences, La Trobe University, P.O. Box 199, Bendigo, VIC, 3552, Australia.

The concept to fight against tumour resistance is to use chemosensitizers that selectively sensitize tumour cells to chemotherapeutic drugs without affecting normal tissue. In this study, the chemosensitizing potential of a novel benzoxazine derivative in combination with Doxorubicin, a DNA damaging chemotherapeutic drug was evaluated. The results of this study showed that the compound LTUR6 is a potent chemosensitizer of Doxorubicin in colon cancer cell lines, HCT116 and HT29. It was also observed that LTUR6 delayed the resolution of Doxorubicin-induced γH2AX, a specific marker of unrepaired DNA DSB, and prolonged cell cycle arrest in both cell lines. This eventually led to DNA fragmentation, caspase activation and ultimately apoptosis in LTUR6 treated cell lines. Results of western blot analysis revealed that LTUR6 significantly inhibited the phosphorylation of DSB repair enzyme AKT, in response to Doxorubicin-induced DSB. We propose that the chemosensitization observed following inhibition of PI3K is likely due to the involvement of a number of downstream targets of AKT.
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http://dx.doi.org/10.1007/s10495-017-1380-4DOI Listing
August 2017

Radiosensitizing activity of a novel Benzoxazine through the promotion of apoptosis and inhibition of DNA repair.

Invest New Drugs 2014 Jun 14;32(3):424-35. Epub 2014 Mar 14.

School of Pharmacy and Applied Science, La Trobe Institute of Molecular Sciences, La Trobe University, P.O. Box 199, Bendigo, VIC, 3552, Australia.

The DNA dependant protein kinase (DNA-PK) enzyme plays a major part in the repair of double stranded breaks induced by radiation and hence in the radio-resistance of tumour cells. Inhibitors of DNA-PK have been tested successfully in the past for their ability to sensitize cancer cells to the effects of radiation. Here we present a novel benzoxazine, 8-methyl-2-(morpholine-4yl)-7-(pyridine-3-methoxy)-4H-1,3-benzoxacine-4-one (LTU27) and analyse its ability to cause sensitization of lung cancer and colon cancer cells to radiation. There was a significant reduction in survival rate, increase in apoptosis and inhibition in autophosphorylation of DNA-PK and AKT1 after treating them concomitantly with both radiation and LTU27. The mechanism of action appears to be through inhibition of DNA-PK leading to delayed DNA repair and promotion of apoptosis.
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http://dx.doi.org/10.1007/s10637-014-0079-4DOI Listing
June 2014

Ethnomedical survey of plants used by the Orang Asli in Kampung Bawong, Perak, West Malaysia.

J Ethnobiol Ethnomed 2010 Feb 7;6. Epub 2010 Feb 7.

School of Pharmacy, Masterskill University College of Health Sciences, Taman Kemacahaya 11, Jalan Kemacahaya, Cheras, Selangor, Malaysia.

Background: A qualitative ethnomedical survey was carried out among a local Orang Asli tribe to gather information on the use of medicinal plants in the region of Kampung Bawong, Perak of West Malaysia in order to evaluate the potential medicinal uses of local plants used in curing different diseases and illnesses.

Methods: Sixteen informants ranging in age from 35 to 65 years were interviewed. A total of 62 species of plants used by Orang Asli are described in this study based on field surveys and direct face to face communication. These plants belonged to 36 families and are used to treat a wide range of discomforts and diseases.

Results: The results of this study showed that majority of the Orang Asli, of Kampung Bawong are still dependent on local plants as their primary source of medication. As the first ethnomedical study in this area, publishing this work is expected to open up more studies to identify and assess the pharmacological and toxicological action of the plants from this region.

Conclusions: Preservation and recording of ethnobotanical and ethnomedical uses of traditional medicinal plants is an indispensable obligation for sustaining the medicinal and cultural resource of mankind. Extensive research on such traditional plants is of prime importance to scientifically validate their ethnomedical claims.
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http://dx.doi.org/10.1186/1746-4269-6-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2843656PMC
February 2010

In vitro screening of anti-lice activity of Pongamia pinnata leaves.

Korean J Parasitol 2009 Dec 2;47(4):377-80. Epub 2009 Dec 2.

School of Pharmacy, Masterskill University College of Health Sciences, Taman Kemacahaya 11, Jalan Kemacahaya, Cheras, Selangor, Malaysia.

Growing patterns of pediculocidal drug resistance towards head louse laid the foundation for research in exploring novel anti-lice agents from medicinal plants. In the present study, various extracts of Pongamia pinnata leaves were tested against the head louse Pediculus humanus capitis. A filter paper diffusion method was conducted for determining the potential pediculocidal and ovicidal activity of chloroform, petroleum ether, methanol, and water extracts of P. pinnata leaves. The findings revealed that petroleum ether extracts possess excellent anti-lice activity with values ranging between 50.3% and 100% where as chloroform and methanol extracts showed moderate pediculocidal effects. The chloroform and methanol extracts were also successful in inhibiting nymph emergence and the petroleum ether extract was the most effective with a complete inhibition of emergence. Water extract was devoid of both pediculocidal and ovicidal activities. All the results were well comparable with benzoyl benzoate (25% w/v). These results showed the prospect of using P. pinnata leave extracts against P. humanus capitis in difficult situations of emergence of resistance to synthetic anti-lice agents.
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http://dx.doi.org/10.3347/kjp.2009.47.4.377DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2788716PMC
December 2009
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