Salinomycin analogs : Mechanistic probes and structure–activity relationships against cancer stem cells
(2016)- Abstract
- Cancer stem cells are a subpopulation of cells that possess an increased tumorigenic potential. Such cells are connected to drug resistance, metastasis, and cancer recurrence. In 2009, the polyether ionophore salinomycin was shown to exhibit selective activity against cancer stem cells. At the outset of the studies described in this thesis, few salinomycin analogs had been reported and it was not known if structural modifications could be used to enhance the activity against cancer stem cells. In addition, the molecular basis for the cancer stem cell selective activity of salinomyin was unknown.
This thesis describes the development of methods for semi–synthesis of salinomycin analogs, and the results of a biological evaluation of... (More) - Cancer stem cells are a subpopulation of cells that possess an increased tumorigenic potential. Such cells are connected to drug resistance, metastasis, and cancer recurrence. In 2009, the polyether ionophore salinomycin was shown to exhibit selective activity against cancer stem cells. At the outset of the studies described in this thesis, few salinomycin analogs had been reported and it was not known if structural modifications could be used to enhance the activity against cancer stem cells. In addition, the molecular basis for the cancer stem cell selective activity of salinomyin was unknown.
This thesis describes the development of methods for semi–synthesis of salinomycin analogs, and the results of a biological evaluation of a library of such analogs in breast cancer cells. Acylation of the C20 hydroxyl group of salinomycin was shown to give structures with enhanced basal toxicity and increased activity against putative breast cancer stem cells. In both functional and marker based assays, the most active analogs gave pronounced effects on the putative cancer stem cell population already at 50 nM concentrations where salinomycin itself did not. Towards a molecular basis of the enhanced activity the structural and ionophore properties of a selection of the most active analogs were investigated. Preparation of a functionally competent fluorescent salinomycin conjugate and its use in a mechanistic investigation is also described.
(Less) - Abstract (Swedish)
- En tredjedel av Sveriges befolkning drabbas av cancer någon gång i livet. När cancerbehandlingar misslyckas beror det oftast på att cancercellerna har utvecklat resistens mot cellgifter eller spridit sig i kroppen och bildat dottertumörer. De senaste årtiondena har forskare intresserat sig för vissa typer av cancerceller som har en extra drivkraft att bilda nya tumörer och sprida sig i kroppen. Sådana celler kan även återbilda alla de olika typer av cancerceller som en tumör vanligen består av. I detta avseende liknar dessa celler vanliga stamceller och har därför kommit att kallas cancerstamceller. Sådana celler har föreslagits vara anledningen till tumörtillväxt, återfall i cancer, och bildandet av dottertumörer. Idag finns det inga... (More)
- En tredjedel av Sveriges befolkning drabbas av cancer någon gång i livet. När cancerbehandlingar misslyckas beror det oftast på att cancercellerna har utvecklat resistens mot cellgifter eller spridit sig i kroppen och bildat dottertumörer. De senaste årtiondena har forskare intresserat sig för vissa typer av cancerceller som har en extra drivkraft att bilda nya tumörer och sprida sig i kroppen. Sådana celler kan även återbilda alla de olika typer av cancerceller som en tumör vanligen består av. I detta avseende liknar dessa celler vanliga stamceller och har därför kommit att kallas cancerstamceller. Sådana celler har föreslagits vara anledningen till tumörtillväxt, återfall i cancer, och bildandet av dottertumörer. Idag finns det inga läkemedel som används för att minska andelen cancerstamceller i tumörer. År 2009 upptäckte en amerikansk forskargrupp att salinomycin, ett antibiotikum som används i stor skala vid kycklinguppfödning, har aktivitet mot bröstcancerstamceller. Detta var en av de första kemiska föreningarna som uppvisade selektiv aktivitet mot cancerstamceller och orsaken till denna selektivitet var okänd. Det är dock vedertaget att den antibiotiska aktiviteten av salinomycin uppnås genom att föreningen binder joner och transporterar dessa genom biologiska membran.
Den här avhandlingen beskriver metoder för att framställa av mer aktiva kemiska derivat av salinomycin. Dessa derivat har också används för att förstå varför föreningarna är aktiva mot cancerstamceller. Genom att framställa ett fluorescerande derivat som går att följa i cellen har vi visat att de mer aktiva derivaten ansamlas i membranet till det endoplasmatiska nätverket (ER), som är cellens lager för kalciumjoner. Trots att salinomycinderivaten inte transporterar kalciumjoner har vi sett att halten av dessa joner ökar i cellen vid behandling med dessa ämnen. Vi har även kunnat visa att de mer effektiva derivaten transporterar natriumjoner snabbare och i större utsträckning än salinomycin. En hypotes som kan förklara den ökade aktiviteten av dessa föreningar är att de transporterar in natrium– och kalium–joner i ER som då släpper ut kalciumjoner i cellen, detta kan i sin tur kopplas till hämmade effekter på cancerstamcellerna.
(Less)
Please use this url to cite or link to this publication:
https://lup.lub.lu.se/record/e6eba68f-5d0f-4a02-94aa-4b9d478197fc
- author
- Borgström, Björn LU
- supervisor
- opponent
-
- Prof. Dr. Kirschning, Andreas, Leibniz University of Hannover, Germany
- organization
- publishing date
- 2016-09
- type
- Thesis
- publication status
- published
- subject
- keywords
- salinomycin, semi–synthesis, ionophore properties, cancer stem cells, fluorescent probe
- pages
- 69 pages
- publisher
- Lund University, Faculty of Science, Department of Chemistry, Centre for Analysis and Synthesis
- defense location
- Center for chemistry and chemical engineering, lecture hall C, Naturvetarvägen 14, Lund
- defense date
- 2016-09-30 13:00:00
- ISBN
- 978-91-7422-472-6
- language
- English
- LU publication?
- yes
- id
- e6eba68f-5d0f-4a02-94aa-4b9d478197fc
- date added to LUP
- 2016-09-02 15:57:23
- date last changed
- 2020-05-11 16:53:01
@phdthesis{e6eba68f-5d0f-4a02-94aa-4b9d478197fc,
abstract = {{Cancer stem cells are a subpopulation of cells that possess an increased tumorigenic potential. Such cells are connected to drug resistance, metastasis, and cancer recurrence. In 2009, the polyether ionophore salinomycin was shown to exhibit selective activity against cancer stem cells. At the outset of the studies described in this thesis, few salinomycin analogs had been reported and it was not known if structural modifications could be used to enhance the activity against cancer stem cells. In addition, the molecular basis for the cancer stem cell selective activity of salinomyin was unknown.<br/><br/>This thesis describes the development of methods for semi–synthesis of salinomycin analogs, and the results of a biological evaluation of a library of such analogs in breast cancer cells. Acylation of the C20 hydroxyl group of salinomycin was shown to give structures with enhanced basal toxicity and increased activity against putative breast cancer stem cells. In both functional and marker based assays, the most active analogs gave pronounced effects on the putative cancer stem cell population already at 50 nM concentrations where salinomycin itself did not. Towards a molecular basis of the enhanced activity the structural and ionophore properties of a selection of the most active analogs were investigated. Preparation of a functionally competent fluorescent salinomycin conjugate and its use in a mechanistic investigation is also described.<br/>}},
author = {{Borgström, Björn}},
isbn = {{978-91-7422-472-6}},
keywords = {{salinomycin; semi–synthesis; ionophore properties; cancer stem cells; fluorescent probe}},
language = {{eng}},
publisher = {{Lund University, Faculty of Science, Department of Chemistry, Centre for Analysis and Synthesis}},
school = {{Lund University}},
title = {{Salinomycin analogs : Mechanistic probes and structure–activity relationships against cancer stem cells}},
year = {{2016}},
}