Multiple myeloma cells are protected against dexamethasone‐induced apoptosis by insulin‐like growth factors

Abstract

Summary. Multiple myeloma cell lines express functional receptors for insulin-like growth factors (IGFs) and several cell types that make up the bone marrow microenvironment produce these cytokines. This suggests that IGFs may play a role in survival and/or expansion of the malignant clone within the marrow in patients with multiple myeloma. We tested the effects of these growth factors on myeloma cells challenged with dexamethasone. Dye exclusion and MTT assays demonstrated that both IGF-I and IGF-II protected the 8226 and dox-40 myeloma cell lines and three primary myeloma cultures from dexamethasone-induced cytotoxicity in a dose-dependent fashion. Morphologic studies of target cells and their nuclei as well as DNA electrophoresis confirmed the IGFs afforded protection against dexamethasone-induced apoptosis. Insulin also protected but was less impressive and required much higher concentrations. IGFs also protected against cycloheximide-induced apoptosis but were ineffective against serum starvation, topoisomerase II inhibitors, or anti-fas antibodies. IGF-induced protection against dexamethasone was not associated with any alteration in quantitative or qualitative expression of BCL-2, BAX or BCL-X proteins. These data indicate that insulin-like growth factors may play a role in maintenance of the malignant clone in patients with myeloma by protecting tumour cells from apoptotic death.

Bisphosphonates antagonise bone growth factors' effects on human breast cancer cells survival

“…Our first experiments showed that when both growth factors and bisphosphonates were simultaneously added to cell cultures, the stimulatory effects of growth factors on cell survival were markedly decreased (for IGFs) or even abolished (for FGF-2). The increased cell survival observed in IGFs-treated cells can be explained by an inhibition of apoptosis, confirmed for example by a decrease in the bax/bcl-2 ratio (Jung et al, 1996;Dunn et al, 1997;Xu et al, 1997). Bisphosphonates could counterbalance these protective effects of bone-derived growth factors on human breast cancer cell survival.…”

Recent insights into the mechanism of glucocorticosteroid-induced apoptosis

“…39,40 Also, interleukin-15 inhibits dexamethasoneinduced apoptosis in activated T and B cells 41 and insulin-like growth factors protect myeloma cells from dexamethasone-induced apoptosis. 42 Thus, a number of different cytokines counteract the induction of apoptosis by corticosteroids ( Figure 4). …”

Blockage of IGF-1R signaling sensitizes urinary bladder cancer cells to mitomycin-mediated cytotoxicity

“…Impairment of its function caused apoptosis of some kinds of cancer cells and inhibition of tumor growth in experimental animals [8,9]. Some investigators also provided evidences that IGF-1R signaling might be implicated in the mechanism of drug resistance in human breast cancer and multiple myeloma [5,10,11]. IGF-1R activation could afford drug protection either by affecting the negative regulators of the apoptosis pathway, Bcl-2 and Bcl-xl, or by altering activity of the ced-3/ICE-like proteases and [12][13][14] p53, the Bcl-protein family are now confirmed and prominent in the mechanism of drug resistance [15,16].…”