Columns (n=3), mean; bars, S.D.*P<0.05;**P<0.01;***P<0.001 compared with VC cells. proapoptotic effect of Gal-3 inhibition, suggesting that calpain activation may be a novel mechanism for the proapoptotic effect of Gal-3 inhibition. Thus, a paradigm shift for treating prostate malignancy is suggested whereby a combination of a Midodrine D6 hydrochloride non-toxic anti-Gal-3 drug together with a harmful chemotherapeutic agent could serve as a novel therapeutic modality for chemoresistant prostate cancers. Keywords:calpain, galectin-3, MCP, prostate malignancy, apoptosis Prostate malignancy is the most common malignancy among men in Western countries. A large number of patients already show metastatic disease at the time of diagnosis. At this stage, prostate malignancy is usually incurable and its growth can only be slowed by hormone deprivation or chemotherapy. Unfortunately, most cases eventually become hormone refractory and chemoresistant.1Therefore, it is important to understand the mechanisms for chemoresistance of prostate cancer, and discover new targets to retrigger the sensitivity of prostate cancer cells to chemotherapeutic drugs. Galectin-3 (Gal-3), a 31 kD carbohydrate-binding protein, is involved in cell growth, Midodrine D6 hydrochloride cell adhesion, invasion, apoptosis and malignancy cell metastasis.2,3,4Increased expression of Gal-3 has been reported during the progression of several human tumors.5,6,7In prostate cancer, Gal-3 protein expression may be decreased compared with normal prostate and prostatic intraepithelial neoplasia.8,9Using differential immunohistochemistry, we recently reported that even though expression level of intact Gal-3 decreased, its cleavage could be associated with the progression of prostate cancer.10Others have found that loss of Gal-3 expression in early stages of prostate malignancy tissues and low aggressive prostate malignancy cell lines was due to the heavy methylation of Gal-3 promoter.11,12In addition, Gal-3 knockdown resulted in reduced cell invasion, cell proliferation, and tumorigenicity of PC3 cells.10Resistance to apoptosis is one of the hallmarks of malignancy cells. The antiapoptotic function of Gal-3 has been well demonstrated in a variety of human cancers, such as breast,13ovarian,14and bladder.15However, data regarding the mode of action of Gal-3 in resistance to drug-induced apoptosis of human prostate malignancy cells are not yet determined, as only a single study reported that overexpression of Gal-3 in Gal-3 null LNCaP cells resulted in the acquisition of resistance to anticancer Rabbit Polyclonal to UBAP2L drug-induced apoptosis.16Another human prostate cancer cell line PC3, which is not sensitive to anticancer drugs, has high expression level of endogenous Gal-3. Therefore, we hypothesized that Gal-3 expression may contribute, in part, to the chemoresistance of prostate malignancy, and that inhibition of Gal-3 using siRNA and/or its antagonist may salvage the sensitivity of prostate malignancy cells to chemotherapy. GCS-100 AKA, altered citrus pectin (MCP), which is the pH-/temperature-modified form of citrus pectin (CP), is usually a highly complex branched polysaccharide rich in galactoside residues. CP is usually water insoluble and is unable to interact with Gal-3, but MCP is usually water soluble and functions as a ligand for Gal-3 competing with its association to natural ligands.17,18,19It was reported that GSC-100/MCP could inhibit the lung colonization,17cellcell and cellmatrix conversation of B16-F1 melanoma cells.18Oral intake of MCP could inhibit the lung metastasis of prostate cancer cells in rat.19GCS-100/MCP feeding inhibited the tumor growth, angiogenesis, and spontaneous metastasis of human breast and colon carcinoma cells in nude mice.20Jacksonet alreported that MCP induced apoptosis in human prostate malignancy cells.21It was also shown that GCS-100/MCP either alone or in combination with dexamethasone inhibits myeloma cells growth, and overcomes drug resistance.22 Cisplatin, a widely used chemotherapeutic agent, is highly effective against several cancers, including testicular, breast, ovarian, bladder, and lung cancers. Late stage prostate malignancy is usually resistant to cisplatin treatment because of the development of chemoresistance.23Cisplatin treatment in Gal-3-expressing PC3 cells could serve as a model to study the relationship between Gal-3 expression and chemoresistance of prostate malignancy cells. Two major apoptotic pathways have Midodrine D6 hydrochloride been defined: death receptor apoptotic.