2-chloroadenosine modulates PAR-1 and IL-23 expression and enhances docetaxel effects on PC3 cells.
BACKGROUND
Docetaxel-based chemotherapy is the only treatment that demonstrated an overall survival benefit in men with hormone refractory prostate cancer. 2-CADO inhibits the growth of PC3 cells by inducing apoptosis and cell cycle arrest through a mechanism that involves cellular uptake.


METHODS
Androgen-independent and -sensitive (PC3 and LNCaP) prostate cancer cells and non-neoplastic HECV cells were used in the study. Proliferation and cell cycle progression were analyzed in the presence of 2-CADO and Docetaxel. Invasive potential was assessed by soft agar assay and metastatic ability by adhesion assay. IL-23 and PAR-1 expression were determined by real time PCR.


RESULTS
2-CADO pre-treatment followed by Docetaxel at subclinical dosage reduced the viability of either PC3 or LNCaP while it did not enhance Docetaxel-induced cytotoxicity in adherent non-neoplastic HECV. The drugs reduced the invasive potential of PC3 cells by inducing apoptosis and blocking cell cycle progression in the S-phase. Down-regulation of PAR-1 gene expression resulted in a slightly lower metastatic potential, whereas up-regulation of IL-23 induced the activation of the immune system.


CONCLUSIONS
Pretreatment of PC3 cells with 2-CADO decreased the effective concentration of Docetaxel, lowered the metastatic potential, and induced the production of cytokines known to stimulate the immune response against cancer. The treatment was effective for prostate cancer cells independently on their androgen sensitiveness.
Minelli
Alba
A
Dipartimento di Medicina Sperimentale Scienze Biochimiche, Sezione Biochimica Cellulare, via del Giochetto, Perugia, Italy.
Bellezza
Ilaria
I
Tucci
Arianna
A
Conte
Carmela
C
Bracarda
Sergio
S
Culig
Zoran
Z
D015762:2-Chloroadenosine / Q000633:toxicity*; D000362:Agar; D000970:Antineoplastic Agents / Q000633:toxicity*; D017209:Apoptosis / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D000077143:Docetaxel; D004357:Drug Synergism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D053760:Interleukin-23 Subunit p19 / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D008297:Male; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D044463:Receptor, PAR-1 / Q000235:genetics* / Q000378:metabolism; D016196:S Phase / Q000187:drug effects; D013234:Stem Cells / Q000187:drug effects; D043823:Taxoids / Q000633:toxicity*
D000970:Antineoplastic Agents; D053760:Interleukin-23 Subunit p19; D044463:Receptor, PAR-1; D043823:Taxoids; D015762:2-Chloroadenosine; D000077143:Docetaxel; D000362:Agar