טכניון מכון טכנולוגי לישראל
הטכניון מכון טכנולוגי לישראל - בית הספר ללימודי מוסמכים  
Ph.D Thesis
Ph.D StudentKedmi-Nachshon Maya
SubjectEffects of Dietary Indole Derivatives on Proliferation of
Prostate Cancer Cells and Investigation of their
Mode of Action
DepartmentDepartment of Biotechnology and Food Engineering
Supervisors Professor Emeritus Shmuel Yannai (Deceased)
Assistant Professor Fuad Fares


Abstract

Prostate cancer (PC) is the second leading cancer-related death in men in Western countries. Hence, efficient anticarcinogenic and therapeutic compounds against PC are badly needed. A number of studies have demonstrated a decreased incidence of various cancers in humans consuming large amounts of cruciferous vegetables, such as broccoli, Brussels sprouts, cabbage and cauliflower. These vegetables contain glucobrassicin which, during metabolism, yields indole-3-carbinol (I3C). The latter may polymerize to form 3,3’-diindolylmethane (DIM). Recently, there is an increased interest in these compounds due to their anticarcinogenic properties.

The objectives of this study were to examine the potential beneficial effects of I3C and DIM on PC cells in vitro, and to examine the potential therapeutic effects of DIM in an in vivo model.

The in vitro model used, examined the effects of I3C and DIM on human PC cell lines with different genetic and histological characteristics - LNCaP (p53 wild type, androgen-dependent, highly differentiated), DU145 (p53 mutant, androgen-independent, moderately differentiated) and PC3 (p53 null, androgen-independent, poorly differentiated). The results indicate that both indole derivatives have a significant inhibitory effect (p < 0.001) on the viability and proliferation of these cells, in a dose- and time-dependent manner. DIM is a more potent compound than I3C, since it exerts its effects more rapidly and at much lower concentrations. Furthermore, the effects of DIM are mediated through the induction of apoptosis in all three cell lines, through a p53, bax, bcl-2 and fasL-independent pathway. Induction of apoptosis in all cells involves activation of the effector caspases 3 and 6 and cleavage of PARP protein. In PC3 cells, the apoptotic process also involves the release of cytochrome C from the mitochondria and the activation of caspase 9.

The in vivo model used examined the therapeutic effects of DIM on tumors, which were induced by subcutaneous injection of TRAMP-C2, a mouse PC cell line, into the flank of male C57BL/6 mice. The results indicate that DIM has a significant inhibitory effect, which is shown by a deceleration in tumor growth and small final tumor weights and volumes. It appears that the mode of action of DIM in vivo involves a decreased rate of cell proliferation and induction of apoptosis.