Dr Alan Richardson

Title: Reader in Pharmacology
Phone: +44 (0)1782 674424
Email: a.richardson1@keele.ac.uk
Location: Institute for Science & Technology in Medicine, Keele University,
Guy Hilton Research Centre, Thornburrow Drive, Hartshill, Stoke-on-Trent ST4 7QB United Kingdom
Role: ISTM Research theme: Therapeutics (Theme lead)
Contacting me: By phone or email
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Following a PhD and post-doctoral work in pharmacology at Cambridge, Alan completed his post-doctoral training at the University of Virginia, USA. Following several years leading drug discovery programs in industry (Johnson & Johnson, Belgium and OSI pharmaceuticals, Oxford) he returned to academic research at the Institute of Cancer Research in London. At Keele, he is module leader and a lecturer on three pharmacology modules and a final year module option on oncology molecular therapeutics. He also makes teaching contributions to the School of Life Sciences and the School of Medicine. He is currently second year tutor.  His research interests focus on discovering new therapeutic targets and drugs for the treatment of ovarian cancer. He has received funding from charities and Research Councils.

ISTM Research theme: Therapeutics

Research interests:

Cancer therapy is entering an exciting era. The fundamental research performed over the last 30 years or so has been translated into new therapies that are now becoming available to treat patients. We are witnessing the arrival of several new “targeted therapies” in the clinic. These targeted therapies differ from traditional chemotherapy by exploiting specific defects in cancer cells. For example, cancer cells may become overly dependent on one particular signalling pathway, and so are susceptible to drugs that target those pathways. Non-cancerous cells may be less dependent on these pathways, and so “normal tissue” may be less sensitive to the effects of the targeted therapies. As a consequence, targeted therapies often have milder side effects than traditional chemotherapy.

But that is not to say that chemotherapy is obsolete. Far from it, in fact. For example, the current therapy for many ovarian cancer patients remains surgery and chemotherapy and this is likely to remain the case until new targeted therapies have been proven in large scale clinical trials to be as effective as chemotherapy. And even after targeted therapies become the preferred treatment option, there will still be a place for chemotherapy. One of the reasons for this is a phenomenon known as drug resistance. After exposure to a drug, cancer cells may become resistant to the effects of the drug. This can occur with both chemotherapy and with the newer targeted therapies. Thus, even when targeted therapies become the standard treatment option, chemotherapy will remain a potent weapon in the clinician’s arsenal to treat disease that has become resistant to a targeted therapy. However, once cancer cells become resistant to chemotherapy, the treatment options may be more limited. One solution to this problem is to develop agents that “reverse” drug resistance – making the cells that are resistant to the drugs sensitive to them once again.

The work in my group is focusing on ovarian cancer.  Many patients initially respond well to chemotherapy, but the emergence of drug resistance may hamper a long-term cure.  To address this, we are pursuing two goals.

Firstly, to identify the molecular mechanisms that lead to drug resistance. This will allow us to identify targets for new drugs that can be used to resensitize drug-resistant cancer cells to chemotherapy. We have conducted a RNAi-based screen, and have identified several genes that appear to contribute to sensitivity to carboplatin and paclitaxel in ovarian cancer cell lines. We are “validating” these as potential drug targets and seeking collaborations to develop drugs inhibiting these targets.

Secondly, we are investigating several new targeted therapies that we anticipate may be used to increase the sensitivity of drug-resistant cancers to chemotherapy. We compare the effects of the chemotherapy alone to the effect of the chemotherapy in combination with a targeted therapy. Where synergy between these two drugs is identified, we seek to identify the underlying molecular mechanism, anticipating that this will help the identification of individual patients who will benefit from combination therapy.

An example of the second approach is shown in the figure below. Cells treated with carboplatin (chemotherapy) are starting to die, but substantially more cells die if they are treated with a combination of carboplatin and ABT-737 (a “BH-3 mimetic” from Abbott laboratories). Chemotherapy can kill cells through a process called apoptosis. ABT-737 prevents the “apoptosis inhibitors” from sequestering the “apoptosis activators” that are generated by carboplatin and that cause cell death by stimulating the “apoptosis effectors” in the mitochondrion. In effect, ABT-737 lowers the threshold for carboplatin to induce cell death by apoptosis.

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Collaborators:

Dr Charles Redman, ISTM Keele and University Hospital of North Staffordshire

Dr Nicholas Forsyth, ISTM, Keele.

Selected Publications

  • Robinson E, Nandi M, Wilkinson LL, Arrowsmith DM, Curtis ADM, Richardson A. 2013. Preclinical evaluation of statins as a treatment for ovarian cancer. Gynecol Oncol, vol. 129(2), 417-424. link> doi>
  • Stamelos VA, Robinson E, Redman CW, Richardson A. 2013. Navitoclax augments the activity of carboplatin and paclitaxel combinations in ovarian cancer cells. Gynecol Oncol, vol. 128(2), 377-382. link> doi>
  • Richardson A, Underwood JK, Allin SM, Redman CW. 2012. Autotaxin - a target for the treatment of drug-resistant ovarian cancer?. In Ovarian cancer - basic science perspective. Farghaly S (Ed.). (vol. 1). Intech. link>
  • Stamelos VA, Redman CW, Richardson A. 2012. Understanding sensitivity to BH3 mimetics: ABT-737 as a case study to foresee the complexities of personalized medicine. J Mol Signal, vol. 7(1), 12. link> doi>
  • Vidot S, Witham J, Agarwal R, Greenhough S, Bamrah HS, Tigyi GJ, Kaye SB, Richardson A. 2010. Autotaxin delays apoptosis induced by carboplatin in ovarian cancer cells. CELLULAR SIGNALLING, vol. 22(6), 926-935. link> doi>

Full Publications List show

Journal Articles

  • Uche FI, Drijfhout FP, McCullagh J, Richardson A, Li W-W. 2016. Cytotoxicity Effects and Apoptosis Induction by Bisbenzylisoquinoline Alkaloids from Triclisia subcordata. Phytother Res, vol. 30(9), 1533-1539. link> doi>
  • Abed MN, Abdullah MI, Richardson A. 2016. Antagonism of Bcl-XL is necessary for synergy between carboplatin and BH3 mimetics in ovarian cancer cells. J Ovarian Res, vol. 9, 25. link> doi>
  • Stamelos VA, Fisher N, Bamrah H, Voisey C, Price JC, Farrell WE, Redman CW, Richardson A. 2016. The BH3 Mimetic Obatoclax Accumulates in Lysosomes and Causes Their Alkalinization. PloS one, vol. 11(3), e0150696. doi>
  • Kitchen MO, Yacqub-Usman K, Emes RD, Richardson A, Clayton RN, Farrell WE. 2015. Epidrug mediated re-expression of miRNA targeting the HMGA transcripts in pituitary cells. Pituitary, vol. 18(5), 674-684. link> doi>
  • Johnson-Ajinwo OR, Richardson A, Li W-W. 2015. Cytotoxic effects of stem bark extracts and pure compounds from Margaritaria discoidea on human ovarian cancer cell lines. Phytomedicine, vol. 22(1), 1-4. link> doi>
  • Richardson A, Curtis ADM, Moss GP, Pearson RJ, White S, Rutten FJM, Perumal D, Maddock K. 2014. Simulated drug discovery process to conduct a synoptic assessment of pharmacy students. Am J Pharm Educ, vol. 78(2), 41. link> doi>
  • Robinson E, Fisher N, Stamelos V, Redman C, Richardson A. 2014. New strategies for the treatment of ovarian cancer. Biochem Soc Trans, vol. 42(1), 125-129. link> doi>
  • Fisher N, Hilton-Bolt T, Edwards MG, Haxton KJ, McKenzie M, Allin SM, Richardson A. 2014. Dendrimer Conjugate of [4-(Tetradecanoylamino)benzyl]phosphonic Acid (S32826) as an Autotaxin Inhibitor. ACS Med Chem Lett, vol. 5(1), 34-39. link> doi>
  • Jain HV, Richardson A, Meyer-Hermann M, Byrne HM. 2014. Exploiting the synergy between carboplatin and ABT-737 in the treatment of ovarian carcinomas. PLoS One, vol. 9(1), e81582. link> doi>
  • Fisher N, Edwards M, Allin S, Richardson A. 2013. AUTOTAXIN INHIBITORS AS A POTENTIAL TREATMENT FOR OVARIAN. INTERNATIONAL JOURNAL OF GYNECOLOGICAL CANCER, vol. 23(8). link>
  • Richardson A and Robinson E. 2013. THE POTENTIAL FOR STATINS IN THE TREATMENT OF OVARIAN CANCER. INTERNATIONAL JOURNAL OF GYNECOLOGICAL CANCER, vol. 23(8). link>
  • Maddock K. 2013. Chairs, bells and students – a novel method to simulate and teach molecular interactions in pharmacology. Pharmacy Education, vol. 13, 36-39. link>
  • Robinson E, Nandi M, Wilkinson L, Arrowsmith M, Curtis ADM, Richardson A. 2013. Preclinical Evaluation of Statins as a Treatment for Ovarian Cancer. Gynecologic Oncology, vol. 129, 417-424. doi>
  • Robinson E, Nandi M, Wilkinson LL, Arrowsmith DM, Curtis ADM, Richardson A. 2013. Preclinical evaluation of statins as a treatment for ovarian cancer. Gynecol Oncol, vol. 129(2), 417-424. link> doi>
  • Richarson A, Bracegirdle L, McLachlan SIH, Chapman SR. 2013. Use of a Three-Dimensional Virtual Environment to Teach Drug-Receptor Interactions. American Journal of Pharmaceutical Education, vol. 77(1), Article 11. doi> link>
  • Richardson A and Robinson E. 2013. The potential for statins in the treatment of ovarian cancer. INTERNATIONAL JOURNAL OF MOLECULAR MEDICINE, vol. 32, S67. link>
  • Stamelos VA, Robinson E, Redman CW, Richardson A. 2013. Navitoclax augments the activity of carboplatin and paclitaxel combinations in ovarian cancer cells. Gynecol Oncol, vol. 128(2), 377-382. link> doi>
  • Yacqub-Usman K, Richardson A, Duong CV, Clayton RN, Farrell WE. 2012. The pituitary tumour epigenome: aberrations and prospects for targeted therapy. Nat Rev Endocrinol, vol. 8(8), 486-494. link> doi>
  • Stamelos VA, Redman CW, Richardson A. 2012. Understanding sensitivity to BH3 mimetics: ABT-737 as a case study to foresee the complexities of personalized medicine. J Mol Signal, vol. 7(1), 12. link> doi>
  • Al-Azzawi H, Yacqub-Usman K, Richardson A, Hofland LJ, Clayton RN, Farrell WE. 2011. Reversal of endogenous dopamine receptor silencing in pituitary cells augments receptor-mediated apoptosis. Endocrinology, vol. 152(2), 364-373. link> doi>
  • Vidot S, Witham J, Agarwal R, Greenhough S, Bamrah HS, Tigyi GJ, Kaye SB, Richardson A. 2010. Autotaxin delays apoptosis induced by carboplatin in ovarian cancer cells. CELLULAR SIGNALLING, vol. 22(6), 926-935. link> doi>
  • Rowther FB, Richardson A, Clayton RN, Farrell WE. 2010. Bromocriptine and dopamine mediate independent and synergistic apoptotic pathways in pituitary cells. Neuroendocrinology, vol. 91(3), 256-267. link> doi>
  • Richardson A and Kaye SB. 2008. Pharmacological inhibition of the Bcl-2 family of apoptosis regulators as cancer therapy. Curr Mol Pharmacol, vol. 1(3), 244-254. link> doi>
  • Witham J, Vidot S, Kaye SB, Richardson A. 2008. Transient ectopic expression as a method to detect genes conferring drug resistance. International Journal of Cancer, vol. 122, 2641-2645. doi>
  • Witham J, Valenti M, De-Haven Brandon A, Vidot S, Eccles S, Kaye S, Richardson A. 2007. The Bcl-2/Bcl-XL Family Inhibitor ABT-737 Sensitizes Ovarian Cancer Cells to Carboplatin. Clinical Cancer Research, vol. 13, 7198. doi>
  • Mortier E, Cornelissen F, van Hove C, Dillen L, Richardson A. 2001. The focal adhesion targeting sequence is the major inhibitory moiety of Fak-related non-kinase. CELLULAR SIGNALLING, vol. 13(12), 901-909. link> doi>
  • Ma A, Richardson A, Schaefer EM, Parsons JT. 2001. Serine phosphorylation of focal adhesion kinase in interphase and mitosis: A possible role in modulating binding to p130(Cas). MOLECULAR BIOLOGY OF THE CELL, vol. 12(1), 1-12. link> doi>
  • Masure S, Haefner B, Wesselink JJ, Hoefnagel E, Mortier E, Verhasselt P, Tuytelaars A, Gordon R, Richardson A. 1999. Molecular cloning, expression and characterization of the human serine/threonine kinase Akt-3. EUROPEAN JOURNAL OF BIOCHEMISTRY, vol. 265(1), 353-360. link> doi>
  • Taylor JM, Richardson A, Parsons JT. 1998. Modular domains of focal adhesion-associated proteins. PROTEIN MODULES IN SIGNAL TRANSDUCTION, vol. 228, 135-163. link>
  • Richardson A, Malik RK, Hildebrand JD, Parsons JT. 1997. Inhibition of cell spreading by expression of the C-terminal domain of focal adhesion kinase (FAK) is rescued by coexpression of Src or catalytically inactive FAK: A role for paxillin tyrosine phosphorylation. MOLECULAR AND CELLULAR BIOLOGY, vol. 17(12), 6906-6914. link> doi>
  • Richardson A, Shannon JD, Adams RB, Schaller MD, Parsons T. 1997. Identification of integrin-stimulated sites of serine phosphorylation in FRNK, the separately expressed C-terminal domain of focal adhesion kinase: A potential role for protein kinase A. BIOCHEMICAL JOURNAL, vol. 324, 141-149. link> doi>
  • Burnham MR, Harte MT, Richardson A, Parsons JT, Bouton AH. 1996. The identification of p130(cas)-binding proteins and their role in cellular transformation. ONCOGENE, vol. 12(11), 2467-2472. link>
  • Richardson A and Parsons JT. 1996. A mechanism for regulation of the adhesion-associated protein tyrosine kinase pp125(FAK). NATURE, vol. 380(6574), 538-540. link> doi>
  • Parsons JT, Richardson A, Hildebrand J, Harte M, Bouton A. 1996. Focal adhesion-associated kinases and cell signalling. JOURNAL OF NEUROCHEMISTRY, vol. 66, S7. link>
  • RICHARDSON A and PARSONS JT. 1995. SIGNAL-TRANSDUCTION THROUGH INTEGRINS - A CENTRAL ROLE FOR FOCAL ADHESION KINASE. BIOESSAYS, vol. 17(3), 229-236. link> doi>
  • RICHARDSON A and TAYLOR CW. 1993. EFFECTS OF CA2+ CHELATORS ON PURIFIED INOSITOL 1,4,5-TRISPHOSPHATE (INSP3) RECEPTORS AND INSP3-STIMULATED CA2+ MOBILIZATION. JOURNAL OF BIOLOGICAL CHEMISTRY, vol. 268(16), 11528-11533. link>
  • OLDERSHAW KA, RICHARDSON A, TAYLOR CW. 1992. PROLONGED EXPOSURE TO INOSITOL 1,4,5-TRISPHOSPHATE DOES NOT CAUSE INTRINSIC DESENSITIZATION OF THE INTRACELLULAR CA2+-MOBILIZING RECEPTOR. JOURNAL OF BIOLOGICAL CHEMISTRY, vol. 267(23), 16312-16316. link>
  • RICHARDSON A, SIMON J, BARNARD EA. 1992. PROTECTION BY OPIOID LIGANDS AGAINST MODIFICATION OF THE OPIOID RECEPTOR BY A CARBODIIMIDE. BIOCHEMICAL PHARMACOLOGY, vol. 43(7), 1415-1419. link> doi>
  • TAYLOR CW and RICHARDSON A. 1991. STRUCTURE AND FUNCTION OF INOSITOL TRISPHOSPHATE RECEPTORS. PHARMACOLOGY & THERAPEUTICS, vol. 51(1), 97-137. link> doi>
  • Li WW, Rosa JO, Siddique MR, Bajana B, Sule-Suso J, Richardson A. 2013. Anti-cancer thymoquinone from Nigella sativa. PLANTA MEDICA, vol. 79(13), 1126. link>
  • PARSONS JT, SCHALLER MD, HILDEBRAND J, LEU TH, RICHARDSON A, OTEY C. 1994. FOCAL ADHESION KINASE - STRUCTURE AND SIGNALING. JOURNAL OF CELL SCIENCE, 109-113. link>
  • Richardson A, Demoliou-Mason C, Barnard EA. Guanine nucleotide-binding protein-coupled and -uncoupled states of opioid receptors and their relevance to the determination of subtypes. Proceedings of the National Academy of Sciences of USA, vol. 89(21), 10198-10202. link>
  • Richardson A and Taylor C. 1992. Purification of the inositol1,4,5-trisphosphate receptor by heparin affinity chromatography using decavandate. Biochem Soc Trans, vol. 20(2), 135S. link> doi>
  • Robinson E, Leung E, Matuszek AM, Krogsgaard-Larsen N, Furkert DP, Brimble MA, Richardson A, Reynisson J. 2015. Virtual screening for novel Atg5-Atg16 complex inhibitors for autophagy modulation. MEDCHEMCOMM, vol. 6(1), 239-246. link> doi>

Chapters

  • Richardson A, Underwood JK, Allin SM, Redman CW. 2012. Autotaxin - a target for the treatment of drug-resistant ovarian cancer?. In Ovarian cancer - basic science perspective. Farghaly S (Ed.). (vol. 1). Intech. link>

Other

  • Uche FI, Li WW, Richardson A, Greenhough TJ. 2014. Anticancer activities of cyclotides from Viola yedeonsis Makino (Violaceae). PLANTA MEDICA (vol. 80, p. 818). link>
  • Uche F, Li WW, Richardson A, Greenhough TJ. 2014. Anti-ovarian cancer activities of alkaloids from Triclisia subcordata olive (Menispermecaea). PLANTA MEDICA (vol. 80, p. 813). link>
  • Richardson M, Robinson E, Turner C, Allin S, Richardson A, Pearson R. 2012. Novel heterocyclic NO-donors as potential anti-cancer agents. NITRIC OXIDE-BIOLOGY AND CHEMISTRY (vol. 27, p. S37). link> doi>
  • Richardson A. 3- phenyl analogs of toxoflavine as kinase inhibitors.
  • Richardson A. 3-furanyl analogs of toxoflavine as kinase inhibitors.
  • Richardson A. Human Akt-3.