Mathematical Modeling of the Role of Survivin on Dedifferentiation and Radioresistance in Cancer.
We use a mathematical model to investigate cancer resistance to radiation, based on dedifferentiation of non-stem cancer cells into cancer stem cells. Experimental studies by Iwasa 2008, using human non-small cell lung cancer (NSCLC) cell lines in mice, have implicated the inhibitor of apoptosis protein survivin in cancer resistance to radiation. A marked increase in radio-sensitivity was observed, after inhibiting survivin expression with a specific survivin inhibitor YM155 (sepantronium bromide). It was suggested that these observations are due to survivin-dependent dedifferentiation of non-stem cancer cells into cancer stem cells. Here, we confirm this hypothesis with a mathematical model, which we fit to Iwasa's data on NSCLC in mice. We investigate the timing of combination therapies of YM155 administration and radiation. We find an interesting dichotomy. Sometimes it is best to hit a cancer with a large radiation dose right at the beginning of the YM155 treatment, while in other cases, it appears advantageous to wait a few days until most cancer cells are sensitized and then radiate. The optimal strategy depends on the nature of the cancer and the dose of radiation administered.
Centre for Mathematical Biology, University of Alberta, Edmonton, Canada.
Adam
A
Rhodes
Centre for Mathematical Biology, University of Alberta, Edmonton, Canada. thillen@ualberta.ca.
Thomas
0000-0003-0819-9520
T
Hillen
D000818:Animals; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000473:pathology / Q000532:radiotherapy; D054337:Cell Dedifferentiation / Q000187:drug effects / Q000502:physiology / Q000528:radiation effects; D045744:Cell Line, Tumor; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D051034:Inhibitor of Apoptosis Proteins / Q000037:antagonists & inhibitors / Q000502:physiology*; D008175:Lung Neoplasms / Q000188:drug therapy / Q000473:pathology / Q000532:radiotherapy; D055641:Mathematical Concepts; D051379:Mice; D008954:Models, Biological; D009285:Naphthoquinones / Q000494:pharmacology; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000473:pathology / Q000528:radiation effects*; D011836:Radiation Tolerance / Q000187:drug effects / Q000502:physiology
D007093:Imidazoles; D051034:Inhibitor of Apoptosis Proteins; D009285:Naphthoquinones; C523798:sepantronium
Cancer stem cells; Dedifferentiation; Radio resistance of cancer; Survivin