Abstract
Hypoxia, a common feature of solid tumors, is a direct stress that triggers apoptosis in many cell types. Poor or irregular tumor vascularization also leads to a decreased drug diffusion and cancer cells distant from blood vessels (hypoxic cells) are exposed to low drug concentrations. In this report, we show that low daunomycin concentrations protect HCT116 colorectal cancer cells from hypoxia-induced apoptosis. While hypoxia induced p53 accumulation without expression of its responsive genes (bax and p21), daunomycin treatment restored p53 transactivation activity and cell cycle progression. We also demonstrated a role for Akt activation in daunomycin-induced protection through phosphorylation and inactivation of the Bcl-2 family proapoptotic factor Bad. Our data therefore suggest that chemotherapy could possibly, because of low concentrations in poorly vascularized tumors, protect cancer cells from hypoxia-induced cytotoxicity.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 50 print issues and online access
$259.00 per year
only $5.18 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Achison M and Hupp TR . (2003). Oncogene, 22, 3431–3440.
Ashcroft M, Taya Y and Vousden KH . (2000). Mol. Cell. Biol., 20, 3224–3233.
Brown JM and Giaccia AJ . (1998). Cancer Res., 58, 1408–1416.
Chao W, Matsui T, Novikov MS, Tao J, Li L, Liu H, Ahn Y and Rosenzweig A . (2003). J. Gene Med., 5, 277–286.
Clark AS, West K, Streicher S and Dennis PA . (2002). Mol. Cancer Ther., 1, 707–717.
Datta SR, Brunet A and Greenberg ME . (1999). Genes Dev., 13, 2905–2927.
Datta SR, Dudek H, Tao X, Masters S, Fu H, Gotoh Y and Greenberg ME . (1997). Cell, 91, 231–241.
del Peso L, Gonzalez-Garcia M, Page C, Herrerra R and Nunez G . (1997). Science, 278, 687–689.
Graeber TG, Osmanian C, Jacks T, Housman DE, Koch CJ, Lowe SW and Giaccia AJ . (1996). Nature, 379, 88–91.
Graeber TG, Peterson JF, Tsai M, Monica K, Fornace Jr AJ and Giaccia AJ . (1994). Mol. Cell. Biol., 14, 6264–6277.
Hirai K, Hayashi T, Chan PH, Zeng J, Yang GY, Basus VJ, James TL and Litt L . (2004). Brain Res. Mol. Brain Res., 124, 51–61.
Kim CY, Tsai MH, Osmanian C, Graeber TG, Lee JE, Giffard RG, DiPaolo JA, Peehl DM and Giaccia AJ . (1997). Cancer Res., 57, 4200–4204.
Koumenis C, Alarcon R, Hammond E, Sutphin P, Hoffman W, Murphy M, Derr J, Taya Y, Lowe SW, Kastan M and Giaccia A . (2001). Mol. Cell. Biol., 21, 1297–1310.
Nicholson KM and Anderson NG . (2002). Cell Signal., 14, 381–395.
Ogawara Y, Kishishita S, Obata T, Isazawa Y, Suzuki T, Tanaka K, Masuyama N and Gotoh Y . (2002). J. Biol. Chem., 277, 21843–21850.
Ogiso Y, Tomida A, Lei S, Omura S and Tsuruo T . (2000). Cancer Res., 60, 2429–2434.
Plo I, Bettaieb A, Payrastre B, Mansat-De Mas V, Bordier C, Rousse A, Kowalski-Chauvel A, Laurent G and Lautier D . (1999). FEBS Lett., 452, 150–154.
Ruscher K, Freyer D, Karsch M, Isaev N, Megow D, Sawitzki B, Priller J, Dirnagi U and Meisel A . (2002). J. Neurosci., 22, 10291–10301.
Sakamuro D, Sabbatini P, White E and Prendergast GC . (1997). Oncogene, 15, 887–898.
Sanna K and Rofstad EK . (1994). Int. J. Cancer, 58, 258–262.
Tanaka M and Grossman HB . (2003). Gene Ther., 10, 1636–1642.
Teicher BA . (1994). Cancer Metast. Rev., 13, 139–168.
Tomida A and Tsuruo T . (1999). Anticancer Drug Des., 14, 169–177.
Vaupel P, Thews O and Hoeckel M . (2001). Med. Oncol., 18, 243–259.
Yamaguchi A, Tamatani M, Matsuzaki H, Namikawa K, Kiyama H, Vitek MP, Mitsuda N and Tohyama M . (2001). J. Biol. Chem., 276, 5256–5264.
Yu J, Wang Z, Kinzler KW, Vogelstein B and Zhang L . (2003). Proc. Natl. Acad. Sci. USA, 100, 1931–1936.
Yu JL, Coomber BL and Kerbel RS . (2002). Differentiation, 70, 599–609.
Zhu Y, Mao XO, Sun Y, Xia Z and Greenberg DA . (2002). J. Biol. Chem., 277, 22909–22914.
Acknowledgements
We thank Drs Yu and Vogelstein for HCT116 P21−/− cells. C Lechanteur is Senior Research Assistant, V Benoît is Research Assistant, A Chariot and M-P Merville are Research Associates of the National Fund for Scientific Research (Belgium). This research was supported by the ‘Leon Fredericq Foundation’, the ‘Centre Anticancéreux près l’ULg’ (Liège, Belgium), and by the Belgian Federation against Cancer.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Lechanteur, C., Jacobs, N., Greimers, R. et al. Low daunomycin concentrations protect colorectal cancer cells from hypoxia-induced apoptosis. Oncogene 24, 1788–1793 (2005). https://doi.org/10.1038/sj.onc.1208436
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/sj.onc.1208436
Keywords
This article is cited by
-
An In Vitro Study of the Neurotoxic Effects of N-Benzylpiperazine: A Designer Drug of Abuse
Neurotoxicity Research (2016)