Title

Anti-Cancer Effect of 2-cyano-3,12 dioxoolean-1,9-dien-28-oic acid (CDDO) Derivatives on Human Multiple Myeloma Cells

Date of Award

5-2018

Degree Type

Thesis

Degree Name

Master of Science in Biomedical Sciences

First Advisor

Xinyu Wang, PhD

Second Advisor

Harold Komiskey, PhD

Third Advisor

Srujana Rayalam, PhD

Abstract

Multiple myeloma (MM) is a blood cell cancer that affects 30,000 people yearly in the U.S. It stems from monoclonal plasma cells and can cause symptoms such as bone loss and fatigue. Recent studies have shown that the bone marrow microenvironment may mediate tumor proliferation, drug resistance, and migration of the multiple myeloma cells. Synthetic oleanane triterpenoids have been readily used in research due to their anti-proliferative and anti-inflammatory effects. The objective of this study is to examine the anti-cancer effect of 2-cyano-3, 12 dioxoolean-1,9-dien-28-oic acid (CDDO) derivatives on human multiple myeloma cells. Three CDDO derivatives (CDDO-Methyl Ester (Me), CDDO-Trifluoethyl Amide (TFEA), and CDDO-Imidazolide (Im) with a dose range from 0.1 to 0.5 µM were tested on the growth of MM RPMI 8226 cells within 72 hours. Our current results show that all CDDO derivatives decrease the cell viability and proliferation of the MM cells in a dose and time-dependent manner. Based on the potency, CDDO-Im was selected to study whether its inhibitory effect on MM cell growth is due to the induction of apoptosis. Western blotting was used to check the protein expression of apoptosis-related factors such as caspase 3, caspase 8, caspase 9 and poly-(ADP-ribose) polymerase (PARP). The result indicates that CDDO-Im may induce the intrinsic apoptotic pathway. To evaluate the effect of CDDO-Im on MM 8226 cells in the presence of the microenvironment, a Transwell (TW) model using MM 8226 cells co-culturing with bone marrow stromal cells was applied to mimic the bone marrow microenvironment in vivo. When treating the HS-5 bone marrow stromal cells alone with CDDO-Im, no significant decrease in proliferation was seen after 24 hours. After co-culturing the MM 8226 cells with HS-5 stromal cells using the TW model, the apoptosis of MM 8226 cells was induced by CDDO-Im. In conclusion, our data suggest that CDDO derivative CDDO-Im inhibits the growth of MM cells through induction of apoptosis in the presence or absence of bone marrow stromal cells.

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