MULTIPLE-MYELOMA CELLS ARE PROTECTED AGAINST DEXAMETHASONE-INDUCED APOPTOSIS BY INSULIN-LIKE GROWTH-FACTORS

Multiple myeloma cell lines express functional receptors for insulin-l ike growth factors (IGFs) and several cell types that make up the bone marrow microenvironment produce these cytokines. This suggests that I GFs may play a role in survival and/or expansion of the malignant clon e within the marrow in patients with multiple myeloma. We tested the e ffects of these growth factors on myeloma cells challenged with dexame thasone. Dye exclusion and MTT assays demonstrated that both IGF-I and IGF-II protected the 8226 and dox-40 myeloma cell lines and three pri mary myeloma cultures from dexamethasone-induced cytotoxicity in a dos e-dependent fashion. Morphologic studies of target cells and their nuc lei as well as DNA electrophoresis confirmed the IGFs afforded protect ion against dexamethasone-induced apoptosis. Insulin also protected bu t was less impressive and required much higher concentrations, IGFs al so protected against cycloheximide-induced apoptosis but were ineffect ive against serum starvation, topoisomerase II inhibitors, or anti-fas antibodies. IGF-induced protection against dexamethasone was not asso ciated with any alteration in quantitative or qualitative expression o f 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 i n patients with myeloma by protecting tumour cells from apoptotic deat h.