Metabolic targeting of hypoxia and HIF1 in solid tumors can enhance cytotoxic chemotherapy

Proceedings of the National Academy of Sciences of the United States of America - Tập 104 Số 22 - Trang 9445-9450 - 2007
Rob A. Cairns1, Ioanna Papandreou2, Patrick D. Sutphin2, Nicholas Denko3
1Division of Radiation and Cancer Biology, Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA 94305, USA
2Division of Radiation and Cancer Biology, Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA 94305
3Stanford University

Tóm tắt

Solid tumors frequently contain large regions with low oxygen concentrations (hypoxia). The hypoxic microenvironment induces adaptive changes to tumor cell metabolism, and this alteration can further distort the local microenvironment. The net result of these tumor-specific changes is a microenvironment that inhibits many standard cytotoxic anticancer therapies and predicts for a poor clinical outcome. Pharmacologic targeting of the unique metabolism of solid tumors could alter the tumor microenvironment to provide more favorable conditions for anti-tumor therapy. Here, we describe a strategy in which the mitochondrial metabolism of tumor cells is increased by pharmacologic inhibition of hypoxia-inducible factor 1 (HIF1) or its target gene pyruvate dehydrogenase kinase 1 (PDK1). This acute increase in oxygen consumption leads to a corresponding decrease in tumor oxygenation. Whereas decreased oxygenation could reduce the effectiveness of some traditional therapies, we show that it dramatically increases the effectiveness of a hypoxia-specific cytotoxin. This treatment strategy should provide a high degree of tumor specificity for increasing the effectiveness of hypoxic cytotoxins, as it depends on the activation of HIF1 and the presence of hypoxia, conditions that are present only in the tumor, and not the normal tissue.

Từ khóa


Tài liệu tham khảo

10.1016/j.semradonc.2004.04.008

JM Brown, AJ Giaccia Cancer Res 58, 1408–1416 (1998).

DM Brizel, SP Scully, JM Harrelson, LJ Layfield, JM Bean, LR Prosnitz, MW Dewhirst Cancer Res 56, 941–943 (1996).

10.1200/JCO.2002.20.3.680

10.1080/02841860410026189

10.1016/j.semradonc.2004.04.002

10.1038/nrc1367

10.1158/1541-7786.MCR-06-0002

10.1128/MCB.25.14.6225-6234.2005

10.1158/0008-5472.CAN-03-2904

10.1126/science.1126863

10.1038/sj.onc.1206703

10.1016/j.ccr.2006.04.023

10.1128/MCB.21.10.3436-3444.2001

GL Semenza, D Artemov, A Bedi, Z Bhujwalla, K Chiles, D Feldser, E Laughner, R Ravi, J Simons, P Taghavi, H Zhong Novartis Found Symp 240, 251–260 (2001).

10.1038/nrc1187

10.1016/j.cmet.2006.01.012

10.1016/j.cmet.2006.02.002

10.1126/science.1088805

10.1158/0008-5472.CAN-05-1235

10.1177/0091270003254637

10.1158/0008-5472.CAN-05-2887

10.1038/nm1294

10.1016/S0360-3016(99)00157-1

10.1016/0360-3016(90)90154-C

10.3109/02841869509093981

10.1038/sj.gt.3301124

10.1016/0360-3016(94)90444-8

CJ Koch Cancer Res 53, 3992–3997 (1993).

10.1023/A:1022939318102

10.1158/0008-5472.CAN-03-3196

10.1016/j.ccr.2005.11.005

10.1038/nature04695

10.1158/0008-5472.CAN-05-2598

10.1200/JCO.2005.05.2878

10.1158/1078-0432.CCR-05-2842

10.1016/j.ccr.2005.06.016

10.1158/1541-7786.MCR-06-0235

10.1016/S0070-2153(06)76007-0

10.1016/j.ccr.2004.06.009

10.1158/0008-5472.CAN-04-3395

Thông tin
Thông tin xuất bản

Proceedings of the National Academy of Sciences of the United States of America

Tập 104 Số 22

9445-9450

Thông tin tác giả