Non-steroidal anti-inflammatory drugs to potentiate chemotherapy effects: From lab to clinic
Introduction
Solid tumors are one of the leading causes of death in the Western countries with an increasing number of cancer patients every year. Although the prognosis of these patients has improved the last decade, there is still a need for novel treatment modalities. Therefore, new targets for anti-cancer treatments are sought. From large retrospective and prospective population-based studies it was learned that regular use of both non-selective non-steroidal anti-inflammatory drugs (NSAIDs), and selective cyclooxygenase-2 (COX-2) inhibitors is associated with an important decreased incidence of colorectal, breast, bladder, prostate as well as lung cancer [1], [2], [3], [4], [5], [6], [7].
Preclinical data suggested that the inhibition of COX-2 is responsible for this decrease in cancer incidence. In addition there is increasing evidence that selective and non-selective COX-2 inhibitors have COX-2 independent effects that can account for the anti-tumor effect of these agents. Moreover, data from cell lines and animal models have shown that NSAIDs in combination with chemotherapy enhances efficacy or can even circumvent drug resistance. Similar findings have been described for NSAIDs in combination with novel molecular targeted therapeutics. This review will focus on potential benefits of selective or non-selective COX-2 inhibitors added to conventional or experimental cancer treatments. COX-2 dependent and COX independent mechanisms for this sensitization will be described.
Section snippets
Cyclooxygenases
Cyclooxygenase (COX) is the enzyme that catalyses the conversion from arachidonic acid to prostaglandins (PGs) [8]. There are three isoforms of COX, COX-1 and COX-3. The COX-1 gene was cloned by three separate groups in 1988 [9], [10], [11]. In 1991, Xie et al. discovered an inducible COX gene named COX-2[12], while COX-3 was discovered in 2002, being a splice variant of COX-1[13]. COX-1 is involved in maintenance of the gastric mucosa, in regulation of renal blood flow in the afferent vessels
COX-2 and carcinogenesis
The role of COX-2 and therefore NSAIDs in cancer development and cancer chemoprevention has been extensively reviewed in the past [37], [38], [39], [40]. To investigate the role of COX-2 in cancer development in more detail a number of COX-2 knock-out models were used. In heterozygous adenomatous polyposis coli (Apc) knock-out mice all the animals develop intestinal polyps [41]. The role of COX-2 expression in this polyp formation was investigated by studying double knock-out mice with a
NSAIDs and radiotherapy
Upregulation of prostaglandin synthesis after irradiation is a tumor protective effect. Selective COX-2 inhibitors have also been described to enhance radiotherapy efficacy primarily by inhibition of angiogenesis [55]. This is a COX-2 dependent effect because neutralization of COX-2 derived PGE2 has the same effect as celecoxib exposure in vivo in Col26 colon cancer cells. In this study, tumor vasculature was measured with contrast magnetic resonance imaging (MRI) [64]. Apart from its
NSAIDs to bypass conventional chemotherapy resistance
One of the first steps to investigate the efficacy of NSAIDs in cancer therapy is to combine them with conventional chemotherapeutic agents. Part of the rationale for combining NSAIDs with chemotherapy involves circumvention of chemotherapy resistance mechanisms.
The Bcl-2 family of pro and anti-apoptotic proteins promotes or inhibits apoptosis at the mitochondrial level. Bcl-2 family members confer a clinically important resistance to chemotherapeutic agents in a number of hematologic and solid
COX-2 expression in normal and malignant tissues
COX-2 is constitutively expressed in the human brain, testis, kidney and central nervous system as well as in premalignant and malignant lesions. COX-2 expression can be rapidly upregulated in macrophages, synoviocytes, fibroblasts, osteoblasts, tumor endothelial cells and “activated” endothelial cells [140]. COX-2 expression is described in several tumor types including, colorectal, gastric, esophageal, hepatocellular, pancreatic, head and neck, non-small cell lung, ovarian, breast, bladder,
NSAIDs in clinical studies and ongoing trials in cancer patients
A number of clinical studies with NSAIDs in cancer patients are available or ongoing. NDAIDs have been investigated in different types of tumors or tumor stages, and different combinations with chemotherapy. Although the focus of clinical oncological research with NSAIDs was on chemoprevention, the last years the potential therapeutic use of NSAIDs in cancer also obtained attention [196]. The preventive use of selective COX-2 inhibitors was extensively investigated in persons carrying the APC
Conclusion
In cell line models NSAIDs in general are potent anti-tumor agents. NSAIDs can inhibit angiogenesis, proliferation, invasive growth, and induce apoptosis in a COX-2 dependent or independent manner. There is a great diversity in mechanisms causing the anti-tumor effect of NSAIDs. The inhibition of PGE2 production as well as the inhibition of transcriptional activity of COX-2 are claimed to be the key mechanisms. However, the concentrations needed to induce COX-2 independent anti-tumor effects
Reviewers
Prof. Mark Hull, Molecular Gastroenterology, University of Leeds, Clinical Sciences Building, St. James's University Hospital, GB-Leeds LS9 7TF, UK.
Dr. Carsten Denkert, Institute of Pathology, Charite Hospital, Campus Mitte, Schumannstrasse 20/21, DE-10117 Berlin, Germany.
Dr. Joanne Jeter, Arizona Cancer Center, 1515 N. Campbell Ave., Rm. 4985, PO Box 245024, Tucson, AZ 85724, USA.
D.J.A. de Groot (1976) received his M.Sc. in medical biology in 2000 at the University of Groningen and started his medical training in 1999 at the University Medical Center Groningen in The Netherlands. He is currently enrolled in the M.D./Ph.D. program of the University Medical Center Groningen in the Research Laboratory of the Department of Medical Oncology. His research interest is in the area of apoptosis and chemotherapy resistance.
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D.J.A. de Groot (1976) received his M.Sc. in medical biology in 2000 at the University of Groningen and started his medical training in 1999 at the University Medical Center Groningen in The Netherlands. He is currently enrolled in the M.D./Ph.D. program of the University Medical Center Groningen in the Research Laboratory of the Department of Medical Oncology. His research interest is in the area of apoptosis and chemotherapy resistance.
S. de Jong (1961) received his M.Sc. in biology in 1986. He studied mechanisms of drug resistance in human small cell lung carcinoma cells at the University Medical Center Groningen. After receiving his Ph.D. in 1991, he worked as a post-doc in the Laboratory of Molecular Genetics of the University of Groningen. He returned to the University Medical Center Groningen in 1995, and became staff member of the Department of Medical Oncology. In 2002 he was a visiting scientist in the Laboratory of Professor J.C. Reed, the Burnham Institute, La Jolla, CA. His research is mainly directed at exploring apoptosis pathways to enhance therapeutic efficacy of cancer treatment.