The regrowth kinetic of the surviving population is independent of acute and chronic responses to temozolomide in glioblastoma cell lines.
Chemotherapy acts on cancer cells by producing multiple effects on a cell population including cell cycle arrest, necrosis, apoptosis and senescence. However, often a subpopulation of cells survives and the behavior of this subpopulation, which is responsible for cancer recurrence, remains obscure. Here we investigated the in vitro short- and long-term responses of six glioblastoma cell lines to clinically relevant doses of temozolomide for 5 days followed by 23 days of recovery, mimicking the standard schedule used in glioblastoma patient for this drug. These cells presented different profiles of sensitivity to temozolomide with varying levels of cell cycle arrest, autophagy and senescence, followed by a regrowth of the surviving cells. The initial reduction in cell number and the subsequent regrowth was analyzed with four new parameters applied to Cumulative Population Doubling (CPD) curves that describe the overall sensitivity of the population and the characteristic of the regrowth: the relative end point CPD (RendCPD); the relative Area Under Curve (rAUC); the Relative Time to Cross a Threshold (RTCT); and the Relative Proliferation Rate (RPR). Surprisingly, the kinetics of regrowth were not predicted by the mechanisms activated after treatment nor by the acute or overall sensitivity. With this study we added new parameters that describe key responses of glioblastoma cell populations to temozolomide treatment. These parameters can also be applied to other cell types and treatments and will help to understand the behavior of the surviving cancer cells after treatment and shed light on studies of cancer resistance and recurrence.
Department of Biophysics, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, RS, Brazil. Electronic address: andrewbiomed@gmail.com.
Andrew Oliveira
AO
Silva
Department of Biophysics, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, RS, Brazil. Electronic address: dalsineloisa@gmail.com.
Eloisa
E
Dalsin
Department of Biophysics, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, RS, Brazil; Center of Biotechnology, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, RS, Brazil. Electronic address: gioonzi@gmail.com.
Giovana Ravizzoni
GR
Onzi
Department of Biophysics, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, RS, Brazil. Electronic address: eduardochiela@gmail.com.
Eduardo Cremonese
EC
Filippi-Chiela
Department of Biophysics, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, RS, Brazil; Center of Biotechnology, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, RS, Brazil. Electronic address: lenz@ufrgs.br.
Guido
G
Lenz
D000818:Animals; D002452:Cell Count; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003606:Dacarbazine / Q000031:analogs & derivatives* / Q000494:pharmacology; D005909:Glioblastoma / Q000473:pathology*; D006801:Humans; D007700:Kinetics; D051379:Mice; D000077204:Temozolomide
D003606:Dacarbazine; D000077204:Temozolomide
Chronic analysis; Cumulative population doubling; Glioblastoma; Surviving cells; Temozolomide