Chemical biology screen for prostate cancer therapeutics

Dissertation

Kirsi Ketola

Research output: ThesisDissertationCollection of Articles

Abstract

Prostate cancer initially responds to hormone-based therapeutics such as anti-androgen treatment or chemotherapeutics but eventually becomes resistant. Novel treatment options are therefore urgently needed. This thesis study applied a high-throughput screen of 4910 known drugs and drug-like small molecules to identify compounds that selectively inhibit growth of prostate cancer cells. In addition, the mechanisms underlying the cellular sensitivity to potent cancer selective compounds were addressed.

Surprisingly, many of the compounds currently used in the clinics or studied in clinical trials were not cancer-selective. Only four drugs, aldehyde dehydrogenase inhibitor disulfiram (Antabus), antibiotic ionophore monensin, histone deacetylase inhibitor tricostatin A and fungicide thiram inhibited prostate cancer cell growth at nanomolar concentrations without major effects on non-malignant prostate epithelial cells. Disulfiram, monensin and a structurally similar compound to monensin, salinomycin, induced oxidative stress and inhibited aldehyde dehydrogenase activity. Moreover, monensin and salinomycin reduced androgen receptor signalling and steroidogenesis, enforced cell differentiation and reduced the overall levels of cancer stem cells. Taken together, novel and potentially prostate cancer-selective therapeutic agents were identified in this study, including the description of a multitude of intoxicating mechanisms such as those relating to oxidative stress. The results provide novel insights into prostate cancer biology and exemplify useful means of considering novel approaches to cancer treatment.
Original languageEnglish
QualificationDoctor Degree
Awarding Institution
  • University of Turku
Supervisors/Advisors
  • Iljin, Kristiina, Supervisor
  • Kallioniemi, Olli, Supervisor, External person
Place of PublicationTurku
Publisher
Print ISBNs978-951-29-4854-3
Electronic ISBNs978-951-29-4855-0
Publication statusPublished - 2011
MoE publication typeG5 Doctoral dissertation (article)

Fingerprint

Monensin
Prostatic Neoplasms
Disulfiram
Aldehyde Dehydrogenase
trichostatin A
Oxidative Stress
Thiram
Pharmaceutical Preparations
Therapeutics
Neoplasms
Histone Deacetylase Inhibitors
Neoplastic Stem Cells
Ionophores
Androgen Receptors
Growth
Androgens
Prostate
Cell Differentiation
Epithelial Cells
Clinical Trials

Keywords

  • prostate cancer
  • oxidative stress
  • androgen receptor
  • disulfiram
  • monensin
  • salinomycin
  • aldehyde dehydrogenase
  • cancer stem cells
  • eturauhassyöpä
  • oksitatiivinen stressi
  • androgeenireseptori
  • disulfiraami
  • monensiini
  • salinomysiini
  • aldehydidehydrogenaasi
  • syöpäkantasolu

Cite this

Ketola, K. (2011). Chemical biology screen for prostate cancer therapeutics: Dissertation. Turku: University of Turku.
Ketola, Kirsi. / Chemical biology screen for prostate cancer therapeutics : Dissertation. Turku : University of Turku, 2011. 46 p.
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Ketola, K 2011, 'Chemical biology screen for prostate cancer therapeutics: Dissertation', Doctor Degree, University of Turku, Turku.

Chemical biology screen for prostate cancer therapeutics : Dissertation. / Ketola, Kirsi.

Turku : University of Turku, 2011. 46 p.

Research output: ThesisDissertationCollection of Articles

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AB - Prostate cancer initially responds to hormone-based therapeutics such as anti-androgen treatment or chemotherapeutics but eventually becomes resistant. Novel treatment options are therefore urgently needed. This thesis study applied a high-throughput screen of 4910 known drugs and drug-like small molecules to identify compounds that selectively inhibit growth of prostate cancer cells. In addition, the mechanisms underlying the cellular sensitivity to potent cancer selective compounds were addressed. Surprisingly, many of the compounds currently used in the clinics or studied in clinical trials were not cancer-selective. Only four drugs, aldehyde dehydrogenase inhibitor disulfiram (Antabus), antibiotic ionophore monensin, histone deacetylase inhibitor tricostatin A and fungicide thiram inhibited prostate cancer cell growth at nanomolar concentrations without major effects on non-malignant prostate epithelial cells. Disulfiram, monensin and a structurally similar compound to monensin, salinomycin, induced oxidative stress and inhibited aldehyde dehydrogenase activity. Moreover, monensin and salinomycin reduced androgen receptor signalling and steroidogenesis, enforced cell differentiation and reduced the overall levels of cancer stem cells. Taken together, novel and potentially prostate cancer-selective therapeutic agents were identified in this study, including the description of a multitude of intoxicating mechanisms such as those relating to oxidative stress. The results provide novel insights into prostate cancer biology and exemplify useful means of considering novel approaches to cancer treatment.

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Ketola K. Chemical biology screen for prostate cancer therapeutics: Dissertation. Turku: University of Turku, 2011. 46 p.