Review Organisms must survive a variety of stress- ful conditions, including sudden temperature increases that damage important cellular struc- tures and interfere with essential functions [1] . In response to stress, cells activate an ancient sig- naling pathway leading to the transient expres- sion of heat stress or heat shock proteins (Hsps) [1] . Hsps are highly conserved proteins that play a vital role in the maintenance of the proteome by assisting the formation of new proteins (so called ‘client proteins’), and preserving existing struc- tures [1,2] . By working as molecular chaperones for several cellular proteins, Hsps are essential for normal cell viability and growth [1,2] . Hsps are abundant proteins in eukaryotic cells with diverse genetic origins [3] . The expression of Hsps is induced in response to a wide variety of physiological and environmental insults, includ- ing anticancer chemotherapy, thus allowing the cell to survive otherwise lethal conditions [4,5] . Cells and organisms as a whole necessarily rely on Hsps for cell adaptation and survival under conditions of stress [1] . There are five classes of Hsps that have chaperone activity. They are named according to their molecular weight (in kilodaltons) [1] : Hsp60, Hsp70, Hsp90, Hsp100 and small Hsps (molecular weight between 12 and 43 kDa). High-molecular weight Hsps are ATP-dependent chaperones, while small Hsps act in an ATP-independent manner [6] . Several mechanisms account for the cytoprotective effect of these stress-inducible Hsps. First, as molecular chaperones, many Hsps catalyze the ATP-dependent holding or folding of cli- ent proteins mediating cell signaling involved in essential processes such as proliferation, cell cycle control, angiogenesis and apoptosis to pre- serve their spatial conformation [2,7,8] . Second, Hsps are themselves powerful anti-apoptotic proteins, associating with key effectors of the apoptotic machinery and, thereby, interfering with this cell death process at different stages [9–12] . Upregulation of Hsps under cell stresses can result from many mechanisms, including the activation of proteins known as heat shock factors (Hsfs) [13] . Hsf1 is normally found in the cytoplasm in its inactive form, bound to Hsps. In stressful events, Hsf1 is thought to dissociate from Hsps and be transported to the nucleus where it binds to specific DNA sequences (heat shock elements) within the promoter region of Hsps, resulting in enhancing Hsp synthesis [13,14] . In vitro, Hsp restrains Hsf1 in mono- mer conformation, and this constraint can be released by immunodepletion or by pharmaco- logical inhibition of the chaperone with specific inhibitors such as geldanomycin or radicicol [13,14] . Although overexpression of Hsp would be expected to suppress Hsf1 activation, as sug- gested in some earlier studies, including Hsp90 [14] , Hsp70 [15,16] and multichaperone complex [17] , this has not been the case in other reports [18] . Also, active Hsf1 mutation shows increased chaperone levels [18] . In addition, it would be Heat shock proteins in cancer: targeting the ‘chaperones’ Heat shock proteins (Hsps) are highly conserved proteins working as molecular chaperones for several cellular proteins essential for normal cell viability and growth, and have numerous cytoprotective roles. The expression of Hsps is induced in response to a wide variety of physiological and environmental stress insults, including anticancer chemotherapy, thus allowing the cell to survive lethal conditions. Cancer cells experience high levels of proteotoxic stress and rely upon stress-response pathways for survival and proliferation, thereby becoming dependent on proteins such as stress-inducible Hsps. Owing to the implication of Hsps in cancer, Hsp inhibition has recently emerged as an interesting potential anticancer strategy. Many natural and synthetic Hsp inhibitors molecular compounds are in development and many are being evaluated as potential cancer therapies. One of the Hsps in particular, Hsp90, has several client proteins and is emerging as a particularly exciting cancer target due to the prospect of simultaneously inhibiting chaperoning of numerous oncogenic proteins. This review describes the function of Hsps focusing on current efforts in exploiting the attributes of Hsps as potential targets for anticancer therapy. Z Nahleh* 1 , A Tfayli 2 , A Najm 3 , A El Sayed 4 & Z Nahle 5 1 Division of Hematology-Oncology, Department of Internal Medicine, TTUHSC-Paul L. Foster School of Medicine, 4800 Alberta Avenue, El Paso, TX 79905, USA 2 American University of Beirut Medical Center, PO Box 11-0236, Riad El Solh, Beirut 1107 2020, Beirut, Lebanon 3 MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030, USA 4 Memorial Medical Center, 2450 S. Telshor Blvd, Las Cruces, NM 88011, USA 5 Vanderbilt University Medical Center, T-4224 MCN, Nashville, TN 37232, USA *Author for correspondence: E-mail: Zeina.nahleh@ttuhsc.edu 927 ISSN 1756-8919 Future Med. Chem. (2012) 4(7), 927–935 10.4155/FMC.12.50 © 2012 Future Science Ltd For reprint orders, please contact reprints@future-science.com