In this study, chemo-sensitivity induced by CLU PI3K Inhibitor Library concentration gene silencing was directly correlated to the endogenous level of CLU protein expressed in a given cell line, being particularly enhanced in KF-TX, SKOV-3-TX, that express the highest levels of s-CLU. An experimental system in which OVK18 cells were genetically modified to specifically over-expression s-CLU rendered cells TX-resistant. Thus, in our system s-CLU seems essential for ovarian cancer cells to resist TX.
Similar results have been obtained in cervical cancer [40]. Thus, up-regulation of s-CLU might be a candidate marker to predict ovarian cancer chemo-resistance, while its reduction after drug administration may predict chemo-response when tumor cells have high endogenous CLU. Importantly, our results support the idea that, s-CLU is a stress-associated cytoprotective protein that is up-regulated in an adaptive cell survival manner following various cell death trigger including chemotherapy in ovarian cancer cells as well as in most cancer cells [41, 35]. Therefore,
novel therapeutic strategy of silencing s-CLU expression to overcome chemoresistance were suggested when cancer cells over-express s-CLU as in lung [42], prostate [43], kidney [44] or breast [13]. In the current study, we firstly demonstrated that OGX-011, a second-generation antisense oligodeoxynuclotide targeting www.selleckchem.com/products/MGCD0103(Mocetinostat).html the translation initiation site of human CLU gene exon II with a long tissue half-life, can modulate sensitivity
to TX in an acquired TX-resistant ovarian cancer cell line. OGX-011 improved the efficacy of chemotherapy, radiation, and hormone withdrawal by inhibiting expression of CLU and enhancing apoptotic rates in preclinical xenograft models of prostate, lung, renal cell, breast, and other cancers [44–46]. Interference with the innate apoptotic activity is a hallmark of neoplastic transformation and tumor formation. Modulation of the apoptotic cascade has been proposed as a new approach for the treatment of cancer. Phenoxodiol [47] and XIAP inhibitor [48] are currently tested in clinical trials as chemosensitizer for chemoresistant tumors [49]. recently reported the result of the phase II study of docetaxel and prednisone with or without OGX-011 in patients with metastatic castration-resistant prostate Adenosine cancer. They have shown that combination of OGX-011 with docetaxel significantly improved survival [49]. We do hope to test the efficacy of OGX-011 as a chemosensitizer to standard cytotoxic drugs for the patients with recurrent (resistant tumor) and refractory ovarian cancer. Conclusions In summary, present study demonstrated that alterations of s-CLU biogenesis are induced during development of TX-resistance. These changes NVP-HSP990 concentration include overexpression inside cells and subsequent secretion into media positively correlates to chemo-resistant phenotype.