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1. An optimised patient-derived explant platform for breast cancer reflects clinical responses to chemotherapy and antibody-directed therapy

Author

Demetriou, Constantinos, Abid, Naila, Butterworth, Michael, Lezina, Larissa, Sandhu, Pavandeep, Howells, Lynne, Powley, Ian R., Pringle, James H., Sidat, Zahirah, Qassid, Omar, Purnell, Dave, Kaushik, Monika, Duckworth, Kaitlin, Hartshorn, Helen, Thomas, Anne, Shaw, Jacqui A., MacFarlane, Marion, Pritchard, Catrin, and Miles, Gareth J.

Published
2024
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9. Mechanisms of action of the chemopreventive agent indole-3-carbinol in breast cell lines

Author

Howells, Lynne M.

Subjects
616.99
Abstract

The chemopreventive agent indole-3-carbinol (I3C) is found in cruciferous vegetables such as broccoli, cabbage and Brussels sprouts. Clinical trials have shown I3C to favourably alter urinary 2-OH:16a estrone ratios, which may prove beneficial for decreased risk of ER+ve breast cancer. However, molecular mechanisms for potential chemopreventive effects in ER-ve breast cancer have yet to be elucidated. I3C inhibited proliferation of the immortalised HBL 100, and tumour-derived MDA MB468, T47D and MCF7 breast cell lines. Approximate IC50s were 122mNm 33mM, 73mM and 67mM respectively, with MDA MB468 cells exhibiting four-fold greater inhibition than HBL 100 cells. I3C caused significant induction of apoptosis in the MDA MB468 cells only, possibly explaining this difference in sensitivity. This was not due to immediate effects upon members of the Bcl-2 family, although downregulation of the anti-apoptotic Bcl-2 protein may have contributed to apoptosis at later time points. I3C caused a dose-dependent decrease in Akt phosphorylation and activity in the MDA MB468 cells, which possessed constitutive Akt activity caused by loss of PTEN expression. I3C was shown to similarly inhibit Akt phosphorylation cell line, but not in the high PTEN/low phospho-Akt expressing Du145 prostate cells or the HBL 100 line. I3C inhibited PI3K activity in the MDA MB468 cells (50mM) and HBL 100 cells (500mM) when added directly into an in vitro kinase assay. Induction of apoptosis in the MDA MB468 and LNCaP cells by the PI3K inhibitor LY294002 supported the hypothesis that inhibition of PI3K signalling may contribute to apoptosis. However, induction of apoptosis by I3C also occurred via an Akt-independent pathway that may involve NF-kB, as I3C, but not LY294002, decreased NF-kB DNA-binding (as shown by EMSA) in the MDA MB468 cells.

Published
2003

10. Clinical trials in cancer screening, prevention and early diagnosis (SPED): a systematic mapping review.

Author

O'Dowd, Emma L., Merriel, Samuel W. D., Cheng, Vinton W. T., Khan, Sam, Howells, Lynne M., Gopal, Dipesh P., Roundhill, Elizabeth A., Brennan, Paul M., Crosbie, Philip A. J., Neal, Richard D., Brown, Karen, Crosbie, Emma J., and Baldwin, David R.

Subjects
EARLY detection of cancer, EARLY diagnosis, CLINICAL trials, MEDICAL screening, LIVER cancer
Abstract

Background: Global annual cancer incidence is forecast to rise to 27.5 M by 2040, a 62% increase from 2018. For most cancers, prevention and early detection are the most effective ways of reducing mortality. This study maps trials in cancer screening, prevention, and early diagnosis (SPED) to identify areas of unmet need and highlight research priorities. Methods: A systematic mapping review was conducted to evaluate all clinical trials focused on cancer SPED, irrespective of tumour type. The National Cancer Research Institute (NCRI) portfolio, EMBASE, PubMed and Medline were searched for relevant papers published between 01/01/2007 and 01/04/2020. References were exported into Covidence software and double-screened. Data were extracted and mapped according to tumour site, geographical location, and intervention type. Results: One hundred seventeen thousand seven hundred one abstracts were screened, 5157 full texts reviewed, and 2888 studies included. 1184 (52%) trials focussed on screening, 554 (24%) prevention, 442 (20%) early diagnosis, and 85 (4%) a combination. Colorectal, breast, and cervical cancer comprised 61% of all studies compared with 6.4% in lung and 1.8% in liver cancer. The latter two are responsible for 26.3% of global cancer deaths compared with 19.3% for the former three. Number of studies varied markedly according to geographical location; 88% were based in North America, Europe, or Asia. Conclusions: This study shows clear disparities in the volume of research conducted across different tumour types and according to geographical location. These findings will help drive future research effort so that resources can be directed towards major challenges in cancer SPED. [ABSTRACT FROM AUTHOR]

Published
2023
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11. Clinical trials in cancer screening, prevention and early diagnosis (SPED): A systematic mapping review

Author

O’Dowd, Emma L, primary, Merriel, Samuel WD, additional, Cheng, Vinton WT, additional, Khan, Sam, additional, Howells, Lynne M, additional, Gopal, Dipesh P, additional, Roundhill, Elizabeth A, additional, Brennan, Paul M, additional, Crosbie, Philip AJ, additional, Neal, Richard D, additional, Brown, Karen, additional, Crosbie, Emma J, additional, and Baldwin, David, additional

Published
2023
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12. Curcumin inhibits cancer stem cell phenotypes in ex vivo models of colorectal liver metastases, and is clinically safe and tolerable in combination with FOLFOX chemotherapy

Author

James, Mark I., Iwuji, Chinenye, Irving, Glen, Karmokar, Ankur, Higgins, Jennifer A., Griffin-Teal, Nicola, Thomas, Anne, Greaves, Peter, Cai, Hong, Patel, Samita R., Morgan, Bruno, Dennison, Ashley, Metcalfe, Matthew, Garcea, Giuseppe, Lloyd, David M., Berry, David P., Steward, William P., Howells, Lynne M., and Brown, Karen

Published
2015
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14. Ex vivo explant model of adenoma and colorectal cancer to explore mechanisms of action and patient response to cancer prevention therapies

Author

Khan, Sam, primary, Miles, Gareth J, additional, Demetriou, Constantinos, additional, Sidat, Zahirah, additional, Foreman, Nalini, additional, West, Kevin, additional, Karmokar, Ankur, additional, Howells, Lynne, additional, Pritchard, Catrin, additional, Thomas, Anne L, additional, and Brown, Karen, additional

Published
2022
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19. Inequalities in cancer screening, prevention and service engagement between UK ethnic minority groups

Author

Abraham, Shalin, primary, Foreman, Nalini, additional, Sidat, Zahirah, additional, Sandhu, Pavandeep, additional, Marrone, Domenic, additional, Headley, Catherine, additional, Akroyd, Carol, additional, Nicholson, Sarah, additional, Brown, Karen, additional, Thomas, Anne, additional, Howells, Lynne M, additional, and Walter, Harriet S, additional

Published
2022
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21. Increased mitochondrial proline metabolism sustains proliferation and survival of colorectal cancer cells

Author

Alaqbi, Saif Sattar, primary, Burke, Lynsey, additional, Guterman, Inna, additional, Green, Caleb, additional, West, Kevin, additional, Palacios-Gallego, Raquel, additional, Cai, Hong, additional, Alexandrou, Constantinos, additional, Myint, Ni Ni Moe, additional, Parrott, Emma, additional, Howells, Lynne M., additional, Higgins, Jennifer A., additional, Jones, Donald J. L., additional, Singh, Rajinder, additional, Britton, Robert G., additional, Tufarelli, Cristina, additional, Thomas, Anne, additional, and Rufini, Alessandro, additional

Published
2022
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26. A Presurgical Study of Curcumin Combined with Anthocyanin Supplements in Patients with Colorectal Adenomatous Polyps

Author

Briata, Irene Maria, primary, Paleari, Laura, additional, Rutigliani, Mariangela, additional, Petrera, Marilena, additional, Caviglia, Silvia, additional, Romagnoli, Paola, additional, Libera, Mauro Dalla, additional, Oppezzi, Massimo, additional, Puntoni, Matteo, additional, Siri, Giacomo, additional, Lazzeroni, Matteo, additional, Howells, Lynne, additional, Singh, Raj, additional, Brown, Karen, additional, and DeCensi, Andrea, additional

Published
2021
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27. Curcumin Combined with FOLFOX Chemotherapy Is Safe and Tolerable in Patients with Metastatic Colorectal Cancer in a Randomized Phase IIa Trial

Author

Howells, Lynne M, Iwuji, Chinenye O O, Irving, Glen R B, Barber, Shaun, Walter, Harriet, Sidat, Zahirah, Griffin-Teall, Nicola, Singh, Rajinder, Foreman, Nalini, Patel, Samita R, Morgan, Bruno, Steward, William P, Gescher, Andreas, Thomas, Anne L, and Brown, Karen

Subjects
Male, Curcumin, Organoplatinum Compounds, curcuminoids, metastatic colorectal cancer, Leucovorin, Administration, Oral, Middle Aged, Treatment Outcome, randomized controlled trial, Antineoplastic Combined Chemotherapy Protocols, FOLFOX chemotherapy, Humans, Female, Original Research Article, Nutrient Physiology, Metabolism, and Nutrient-Nutrient Interactions, Fluorouracil, Neoplasm Metastasis, Colorectal Neoplasms, Aged
Abstract

Background Curcumin is the main active ingredient of the spice turmeric, investigated extensively for putative anticancer properties. Objectives This phase IIa open-labelled randomized controlled trial aimed to assess safety, efficacy, quality of life, neurotoxicity, curcuminoids, and C-X-C-motif chemokine ligand 1 (CXCL1) in patients receiving folinic acid/5-fluorouracil/oxaliplatin chemotherapy (FOLFOX) compared with FOLFOX + 2 g oral curcumin/d (CUFOX). Methods Twenty-eight patients aged >18 y with a histological diagnosis of metastatic colorectal cancer were randomly assigned (1:2) to receive either FOLFOX or CUFOX. Safety was assessed by Common Toxicity Criteria-Adverse Event reporting, and efficacy via progression-free survival (PFS) and overall survival (OS). Quality of life and neurotoxicity were assessed using questionnaires (European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-C30 and Functional Assessment of Cancer Treatment-Gynecologic Oncology Group-Neurotoxicity). Plasma curcuminoids were determined with liquid chromatography (LC) electrospray ionization tandem mass spectrometry and CXCL1 by ELISA. Results Addition of daily oral curcumin to FOLFOX chemotherapy was safe and tolerable (primary outcome). Similar adverse event profiles were observed for both arms. In the intention-to-treat population, the HR for PFS was 0.57 (95% CI: 0.24, 1.36; P = 0.2) (median of 171 and 291 d for FOLFOX and CUFOX, respectively) and for OS was 0.34 (95% CI: 0.14, 0.82; P = 0.02) (median of 200 and 502 d for FOLFOX and CUFOX, respectively). There was no significant difference between arms for quality of life (P = 0.248) or neurotoxicity (P = 0.223). Curcumin glucuronide was detectable at concentrations >1.00 pmol/mL in 15 of 18 patients receiving CUFOX. Curcumin did not significantly alter CXCL1 over time (P = 0.712). Conclusion Curcumin is a safe and tolerable adjunct to FOLFOX chemotherapy in patients with metastatic colorectal cancer. This trial was registered at clinicaltrials.gov as NCT01490996 and at www.clinicaltrialsregister.eu as EudraCT 2011-002289-19.

Published
2019

37. Endothelial Progenitor Cells are Increased in Patients with Advanced Pancreatic Cancer Treated with Gemcitabine and Intravenous Omega 3 Compared with Controls

Author

Isherwood, John, primary, Arshad, Ali, additional, Chung, Wen, additional, Runau, Franscois, additional, Cooke, Jill, additional, Pollard, Cristina, additional, Howells, Lynne, additional, Fishwick, Jenny, additional, Thompson, John, additional, Metcalfe, Matthew, additional, Steward, William, additional, and Dennison, Ashley, additional

Published
2020
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38. Myeloid derived suppressor cells are reduced and T regulatory cells stabilised in patients with advanced pancreatic cancer treated with gemcitabine and intravenous omega 3

Author

Isherwood, John, primary, Arshad, Ali, additional, Chung, Wen Yuan, additional, Runau, Franscois, additional, Cooke, Jill, additional, Pollard, Cristina, additional, Howells, Lynne, additional, Fishwick, Jenny, additional, Thompson, John, additional, Metcalfe, Matthew, additional, Steward, William, additional, and Dennison, Ashley, additional

Published
2020
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43. Additional file 1: Figure S1a-d. of Effects of OmegavenÂŽ, EPA, DHA and oxaliplatin on oesophageal adenocarcinoma cell lines growth, cytokine and cell signal biomarkers expression

Author

Eltweri, Amar, Howells, Lynne, Thomas, Anne, Dennison, Ashley, and Bowrey, David

Abstract

Figure S1a: Effects of EPA treatment on OE19 (A) and OE33 (B) cell line growth at four time points. Figure S1b: Effects of DHA treatment on OE19 (A) and OE33 (B) cell growth at four time points. Figure S1c: Effects of Oxaliplatin treatment on OE19 (A) and OE33 (B) cell lines growth at four time points. Figure S1d: Effects of OmegavenÂŽ treatment on OE19 (A) and OE33 (B) cell lines growth at four time points. (DOCX 285 kb)

Published
2018
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44. Growth-inhibitory effects of the chemopreventive agent indole-3-carbinol are increased in combination with the polyamine putrescine in the SW480 colon tumour cell line

Author

Gescher Andreas, Gallacher-Horley Barbara, Fox Louise H, Howells Lynne M, Hudson E Ann, and Manson Margaret M

Subjects
Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Abstract Background Many tumours undergo disregulation of polyamine homeostasis and upregulation of ornithine decarboxylase (ODC) activity, which can promote carcinogenesis. In animal models of colon carcinogenesis, inhibition of ODC activity by difluoromethylornithine (DFMO) has been shown to reduce the number and size of colon adenomas and carcinomas. Indole-3-carbinol (I3C) has shown promising chemopreventive activity against a range of human tumour cell types, but little is known about the effect of this agent on colon cell lines. Here, we investigated whether inhibition of ODC by I3C could contribute to a chemopreventive effect in colon cell lines. Methods Cell cycle progression and induction of apoptosis were assessed by flow cytometry. Ornithine decarboxylase activity was determined by liberation of CO2 from 14C-labelled substrate, and polyamine levels were measured by HPLC. Results I3C inhibited proliferation of the human colon tumour cell lines HT29 and SW480, and of the normal tissue-derived HCEC line, and at higher concentrations induced apoptosis in SW480 cells. The agent also caused a decrease in ODC activity in a dose-dependent manner. While administration of exogenous putrescine reversed the growth-inhibitory effect of DFMO, it did not reverse the growth-inhibition following an I3C treatment, and in the case of the SW480 cell line, the effect was actually enhanced. In this cell line, combination treatment caused a slight increase in the proportion of cells in the G2/M phase of the cell cycle, and increased the proportion of cells undergoing necrosis, but did not predispose cells to apoptosis. Indole-3-carbinol also caused an increase in intracellular spermine levels, which was not modulated by putrescine co-administration. Conclusion While indole-3-carbinol decreased ornithine decarboxylase activity in the colon cell lines, it appears unlikely that this constitutes a major mechanism by which the agent exerts its antiproliferative effect, although accumulation of spermine may cause cytotoxicity and contribute to cell death. The precise mechanism by which putrescine enhances the growth inhibitory effect of the agent remains to be elucidated, but does result in cells undergoing necrosis, possibly following accumulation in the G2/M phase of the cell cycle.

Published
2003
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50. Curcumin mediates oxaliplatin-acquired resistance reversion in colorectal cancer cell lines through modulation of CXC-Chemokine/NF-κB signalling pathway

Author

Ruiz de Porras, Vicenç, primary, Bystrup, Sara, additional, Martínez-Cardús, Anna, additional, Pluvinet, Raquel, additional, Sumoy, Lauro, additional, Howells, Lynne, additional, James, Mark I., additional, Iwuji, Chinenye, additional, Manzano, José Luis, additional, Layos, Laura, additional, Bugés, Cristina, additional, Abad, Albert, additional, and Martínez-Balibrea, Eva, additional

Published
2016
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