Abstract
Prostate cancer (PCA) is the most common malignancy and the second leading cause of cancer-related deaths among men in the United States. The advances in the field of chemotherapy, radiotherapy and hormonal therapy have been insufficient to lower the burden of this malignancy, and therefore alternative measures are urgently warranted against PCA. The use of phytochemicals in cancer chemoprevention and intervention has emerged as an attractive alternative strategy for various malignancies including PCA. Recently, we isolated novel water soluble high molecular weight (>1000kDa) fractions from the roots of Caucasian species of Comfreynamely Symphytum asperum (HM-SAR) and Symphytum caucasicum (HM-SCR) by ultrafiltration. UV, IR and NMR spectral data confirmed caffeic acid-derived polymer - poly[3-(3,4-dihydroxyphenyl)glyceric acid] as the main chemical constituent of HM-SAR and HM-SCR. We also synthesized the monomer syn-2,3-dihydroxy-3-(3,4-dihydroxyphenyl) propionic acid (DDPPA) of this polymer. Next, we examined the anticancer efficacy of HM-SAR, HM-SCR and DDPPA in androgen-dependent (LNCaP) and -independent (22Rv1 and PC3) human PCA cells. Our results showed that HM-SAR treatment (100 \#956;g/ml for 48h) decreases live cell number by 65, 64 and 35% (p< 0.001) and increases cell death by 16, 8 and 12 folds (p< 0.01 to p< 0.001) in LNCaP, 22Rv1 and PC3 cells, respectively. Similarly, HM-SCR (100 \#956;g/ml for 48h) decreased the live cell number by 87, 25 and 33% (p< 0.001) and increased cell death by 19, 10 and 9 folds (p< 0.01 to p< 0.001) in LNCaP, 22Rv1 and PC3 cells, respectively. DDPPA treatment (100 \#956;g/ml for 48h) decreased live cell number by 29, 89 and 28% (p< 0.01 to p< 0.001) and increased cell death by 11, 34 and 9 folds in LNCaP, 22Rv1 and PC3 cells, respectively (p< 0.001). FACS analysis showed that these compounds differentially modulate cell cycle progression in PCA cells, which was based upon dose, treatment duration and cell type. HM-SAR (1-100 \#956;g/ml) caused a significant G1-phase arrest after 24 and 48h of treatment accompanied with a decrease in S-phase population in both PC3 and LNCaP cells (p< 0.05 to p< 0.001). HM-SCR treatment (1-100 \#956;g/ml) for 72h in PC-3 cells resulted in a strong S-phase arrest (p< 0.05 to p< 0.01); while in LNCaP cells it caused a moderate G1-phase arrest at lower doses (1-50 \#956;g/ml), and a strong G2M-phase arrest at higher dose (100 \#956;g/ml)(p< 0.05 to p< 0.001). DDPPA treatment (1-100 \#956;g/ml) in PC3 cells caused a strong S-phase arrest and slight G2M-phase arrest; while in LNCaP cells DDPPA (1-100 \#956;g/ml) caused a moderate G1-phase arrest (p< 0.05 to p< 0.001). Overall, present study identified the strong efficacy of these novel phytochemicals against PCA cells, and suggested that their pre-clinical efficacy studies in PCA models are needed in future to move them forward for possible translational potential in PCA patients.
Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 921.
100th AACR Annual Meeting-- Apr 18-22, 2009; Denver, CO