Cell Cycle Arrest by Glucocorticoids May Protect Normal Tissue and Solid Tumors from Cancer Therapy

Abstract

ABBrevIAtIons DEX ABstrActGlucocorticoids have been widely used as cotreatment for patients with cancer due to potent pro-apoptotic properties in lymphoid cells, reduction of nausea and diminishing acute toxicity on normal tissue. There are now data from preclinical and, to some extent, clinical studies, demonstrating that these medicaments are highly suspicious to induce therapy resistance in the majority of malignant solid tumors-irrespective of tumor origin and the nature of specific anticancer drugs or irradiation used for treatment. Despite these huge amounts of data, the underlying mechanisms of cell type-specific signaling by these steroid hormones are just beginning to be described. This review summarizes our present understanding of a relationship between glucocorticoid-induced reversible cell cycle arrest and therapy resistance in solid tumors. We give a summary of our current knowledge of decreased proliferation rates in response to glucocorticoid pre and combination treatment which are suspicious to be involved not only in protection of normal tissues, but also in protection of solid tumors from cytotoxic effects of anticancer agents. The inhibition of cell cycle progression by pretreatment with GCs may be crucially involved in switching the balance of several interacting pathways to survival upon treatment with GCs.

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

“…So, Dex-induced cell growth inhibition and cell cycle arrest in G1 may also be one of the mechanisms of its anti-apoptotic effect on cancer therapy. Mattern et al (2007) held a similar opinion that the inhibition of cell growth by inducing cell cycle arrest may be crucially involved in switching the balance of several interacting pathways to survival upon treatment with GCs.…”

Glucocorticoids and circadian clock control of cell proliferation: At the interface between three dynamic systems

“…Glucocorticoids have been described to act both as stimulators and inhibitors of cell proliferation, depending on the cell type and the concentrations used (reviewed in [117]). In general, it appears that a lower concentration of dexamethasone can stimulate cell growth, whereas higher doses inhibit proliferation.…”

“…Some of the mechanisms proposed for this cell cycle arrest are glucocorticoid mediated repression of cyclin D3 and cmyc, negative crosstalk of the GR with p53, and glucocorticoid mediated induction of the cyclin dependent kinase inhibitors p21 WAF1/CIP1 and p27 kip (reviewed in [117,118]). As mentioned above, both p21 and c-myc are also targets of circadian clock control, thus providing potential candidates for a direct cross talk of circadian clock regulation with glucocorticoid signalling.…”

“…Glucocorticoid mediated induction of apoptosis and cell cycle arrest have long been exploited for therapy (reviewed in [117,165,166]). Thus, the glucocorticoid mediated induction of apoptosis in the blood cell lineage is exploited for the treatment of leukaemia.…”

“…Thus, in glucocorticoid sensitive tumours, therapy can be negatively affected, because non-proliferating cells are less vulnerable to chemotherapy. Also radiotherapy can be impaired by the G1 arrest, since the sensitivity of cells to radiotherapy is highest at M phase [117]. In this scenario a chronotherapeutic approach might prove particulary useful: One could administer glucocorticoids and chemo-or radiotherapy with a distinct time profile that would retain at least some of the beneficial effects of glucocorticoids while avoiding their effects on the cell cycle at the time of therapy.…”