Dexamethasone-induced cisplatin and gemcitabine resistance in lung carcinoma samples treated ex vivo

Abstract

Chemotherapy for lung cancer not only has severe side effects but frequently also exhibits limited, if any clinical effectiveness. Dexamethasone (DEX) and similar glucocorticoids (GCs) such as prednisone are often used in the clinical setting, for example, as cotreatment to prevent nausea and other symptoms. Clinical trials evaluating the impact of GCs on tumour control and patient survival of lung carcinoma have never been performed. Therefore, we isolated cancer cells from resected lung tumour specimens and treated them with cisplatin in the presence or absence of DEX. Cell number of viable and dead cells was evaluated by trypan blue exclusion and viability was measured by the MTT-assay. We found that DEX induced resistance toward cisplatin in all of 10 examined tumour samples. Similar results were found using gemcitabine as cytotoxic drug. Survival of drug-treated lung carcinoma cells in the presence of DEX was longlasting as examined 2 and 3 weeks after cisplatin treatment of a lung carcinoma cell line. These data corroborate recent in vitro and in vivo xenograft findings and rise additional concerns about the widespread combined use of DEX with antineoplastic drugs in the clinical management of patients with lung cancer. British Journal of Cancer (2005) The incidence of lung cancer has increased considerably over the past 50 years and lung carcinoma has become the leading cause of death by cancer in both men and women (Levi et al, 2004). The prognosis is still poor and about 80% of patients die within 1 year of diagnosis (Office for National Statistics, 1997). Despite some advances in surgical procedures, chemotherapy and radiotherapy made over the past two decades, long-term survival in, for example, non-small-cell lung cancer (NSCLC) patients at stage 3 and 4 is obtained in only 5 -10% of cases (Cancer Research UK, 2004). The development of drug resistance in patients receiving chemotherapy or a combination therapy including ionizing radiation represents a major problem in cancer treatment. The present paper aims at addressing one aspect of this complex problem. Dexamethasone (DEX) and similar glucocorticoids (GCs) were first introduced to tumour therapy on the basis of proapoptotic effects in lymphoid cells and on their effectiveness in treating tumour-related oedema, inflammation, pain and electrolyte imbalance as well as stimulating appetite, and most importantly, preventing nausea and emesis caused by cytotoxic drugs (Aapro, 1991;Cheng et al, 1997;Kirkbride et al, 2000; The Italian Group of Anticancer Research, 1995, 2000. However, prospective randomised trials evaluating a potential impact on tumour control and patient survival have never been performed. Induction of apoptosis resistance toward chemotherapy by DEX was recently described in a cervical and a lung carcinoma cell line (Herr et al, 2003) as well as in a breast cancer cell line (Wu et al, 2004). In vivo, a xenografted and cisplatin-treated lung tumour cell line grew faster in the presence of DEX (Herr et al, 2003). These results and earl...

Does dexamethasone inhibit anticancer activity of cetuximab in squamous cell carcinoma cell lines of the head and neck?

“…So these findings are partially in contrast to those reported by Zhang et al (19) who demonstrated glucocorticoid-induced resistance to chemotherapy in the majority of cell lines derived from various malignancies including brain, breast, cervix, melanoma and neuroblastoma. Gassler et al (14) found an anti-apoptotic effect of glucocorticoids in tissue samples from lung cancer. Glucocorticoids are also highly likely to induce resistance and accelerated tumor growth in patients with prostate, renal cell, bladder and testicular cancer (20).…”

“…However, in the past few years several publications have discussed the potential of glucocorticoids like dexamethasone to induce resistance to antineoplastic agents (14,15). Thus, the question arises if dexamethasone used to prevent or treat allergic reactions to cetuximab may also lead to resistance to the agent in the treatment of SCCHN.…”

Dexamethasone enhances cell resistance to chemotherapy by increasing adhesion to extracellular matrix in human ovarian cancer cells

“…Recently, more and more data from preclinical studies, and to some extent from clinical studies, have strongly recommended a GC-conferred resistance to cancer therapy in the majority of malignant solid tumors -irrespective of tumor origin and the nature of specific anticancer drugs (Wolff et al 1996, Weller et al 1997, Webster et al 2002, Herr et al 2003, Wu et al 2004, Gassler et al 2005, Runnebaum & Brüning 2005, Sui et al 2006, Zhang et al 2006a,b,c,d,e, 2007. In this study, we have demonstrated that Dex could protect human ovarian IgG (10 µg/ml) Anti-β1 (µg/ml) Figure 4 Dex-enhanced cell attachment and cell survival are partially reversed by integrin b1-blocking antibody.…”

“…More recent data indicate that GCs can inhibit apoptosis induced by chemotherapy not only in established cancer cell lines and tumor xenografts, but also in the freshly isolated cells from surgical resections from tumors of various origins, including ovary, breast, prostate, pancreas, liver, colon, brain, cervix, bone, skin, and nervous system (Herr et al 2003, Sui et al 2006, Zhang et al 2006a. In addition, the anti-chemotherapeutic effect of GCs can be seen in several anticancer drugs including cisplatin (Wolff et al 1996, Gassler et al 2005, Zhang et al 2006a,b,d, 2007, paclitaxel (Wu et al 2004, Sui et al 2006, 5-fluorouracil (Zhang et al 2006a(Zhang et al , 2007, adriamycin (Weller et al 1997), actinomycin D (Wolff et al 1996), doxorubicin (Wu et al 2004), and gemcitabine (Gassler et al 2005, Zhang et al 2007). The GC-induced pro-survival effects should be of important clinical relevance when they interfere with the effect of chemotherapeutics.…”

Improved lentiviral transduction of human mesenchymal stem cells for therapeutic intervention in pancreatic cancer

“…After treatment, the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium (MTT) assay was performed as recently described. 27 Migration to chemoattractants measured by transwell chamber migration assay A ChemoTx System (Neuro Probe Inc., Gaithersburg, MD, USA) with 96 wells was used for the migration assay. The polycarbonate membrane pore size of 12 mm was selected to allow passage of mammalian cells.…”