Download Identifying Compounds that Synergizes with FTY720 Analogs to Kill

Identifying Compounds that Synergizes with FTY720 Analogs to Kill Castrate Resistant Prostate
Cancer Cells
Gina Banh
Mentor: Aimee L. Edinger
FTY-720 is an FDA approved drug for multiple sclerosis in humans, which is also known to have anti-cancer
activity. One mechanism it uses to kill cancer cells is down regulating nutrient transporters from the cell
surface. The loss of transporter proteins results in starvation of the cancer cell and, ultimately, death.
Although it can be used for anti-cancer activity, it has known side effects such as bradycardia and lymphocyte
sequestration. To avoid those side effects, we developed FTY-720 analogs that lack its toxicity. These
compounds are active as single agents, but it is widely recognized that combination reactions can increase
efficacy while lowering toxicity. To test if combinations of different drugs will provide synergistic effects at
lower doses, I combined SH-BC-893, an FTY-720 analog, with chloroquine and Secin-H3, a drug that
prevents endosome recycling. I used PC3 cells, a PTEN null and androgen receptor null prostate cancer cell
line. I treated the cells with different combinations and performed: (1) viability and proliferation, and (2) 4F2heavy-chain protein transporter chaperone expression assays using flow cytometry. I found that SH-BC-893
is able to produce greater cell death when combined with Secin-H3 by maintaining a longer effect on nutrient
transporter loss. Viability assays using SH-BC-893 combined with both chloroquine and Secin-H3 resulted in
even greater synergy. The synergistic abilities of these drugs at lower concentrations in PC3 cells provide
possible new therapeutic treatments for patients with castration resistant prostate cancer by inducing death in
cancer cells while lowering toxic side-effects in normal human cells.