shock proteins (HSPs) are a super family of highly conserved molecular

shock proteins (HSPs) are a super family of highly conserved molecular chaperone proteins which are induced in response to stress. resistant MM cells. 1989 Preisler1989b). Improved survival requires new strategies to prevent relapse. An increasing body of evidence suggests that the bone marrow microenvironment is the primary site for minimal residual disease (MRD) leading to relapse after chemotherapy (Matsunaga2003 Preisler1989a). Adhesion of MM cells to extra-cellular matrix (ECM) components BMP2 such as fibronectin (FN) via β1 integrin has been demonstrated to confer resistance to a host of chemotherapeutic agents (Damiano1999 Shain2000). This anti-apoptotic phenomenon termed “cell adhesion-mediated drug resistance” (CAM-DR) is a form of drug resistance (Damiano1999 Shain2000). Therefore identification of mediators of cell adhesion may elucidate novel targets for MM therapy and inhibition of this target could potentially overcome CAM-DR. In addition to CAM-DR chemo-resistance in MM is characterized by a concomitant insensitivity to CGP77675 the drugs used in therapy as well as to other unrelated cytotoxic agents – a phenomenon known as acquired multidrug resistance (MDR) (Bellamy1991 Bhalla1994 Dalton1986 Ross 2000). This acquired drug resistance has been shown to develop following chemotherapy. Recently our group has reported genotypic and phenotypic profiles of acquired and melphalan resistance in an isogenic human myeloma cell line (Hazlehurst2003). Gene expression changes associated with resistance were significantly less complex compared with CGP77675 acquired resistance (Hazlehurst2003). This indicates that myeloma cell adhesion promotes a form of drug resistance by protecting cells from melphalan-induced cytotoxic damage and that this transient protection allows cells to acquire a more permanent and complex drug resistance phenotype associated with a reduction in drug induced DNA damage. Heat shock proteins (HSPs) are highly conserved proteins which are induced in plant yeast bacterial and mammalian cells in response to an array of physiological and environmental stress cues (Welch 1992). CGP77675 HSP70 has been shown to be preferentially expressed in high-grade malignant tumors compared to low-grade tumors and surrounding tissues (Ralhan and Kaur 1995 Santarosa1997). HSP70 was also associated with chemotherapeutic resistance in many forms of leukemias (Chant1995 Santarosa1997 Sliutz1996). Though heat shock proteins were initially discovered to function as molecular chaperones there is increasing evidence to suggest that they play a key role in survival of cancer cells (Beere2000 Jaattela1998). HSP70 has been reported to prevent cell death initiated by various apoptotic stresses CGP77675 such as heat shock ceramide ionizing radiation tumour necrosis factor-alpha (TNF-α) and ischemia (Geginat1993) (Jaattela1998). Further HSP70 has been shown to inhibit mitochondria-induced apoptosis by physically interacting with and inhibiting Apaf-1 and apoptosis-inducing factor (AIF) resulting in suppression of caspase-dependent and -independent apoptosis respectively (Beere2000 Ravagnan2001). In spite of the extensive studies of HSP70 in apoptosis and drug resistance there is lack of information on its role in tumor microenvironment and MRD in cancer therapy. The present study demonstrated CGP77675 that HSP70 expression was enhanced when 8226 myeloma cells were attached to stromal cells. HSP70 CGP77675 inhibition reduced adhesion of myeloma cells to FN or stromal cells caused apoptosis of acquired and drug resistant myeloma cells and sensitized them to..