Influencing the Wnt Signaling Pathway in Multiple Myeloma

Outline

• Abstract
• Keywords
• Multiple Myeloma
• Wnt Signaling Pathway
• β-Catenin
• Wnt Pathway Signaling in Mm
• Dkk1 and Mm Bone Disease
• Targeting the Wnt Pathway in Myeloma
• Acknowledgements
• References

Targeting the Wnt Pathway in Myeloma

The Wnt/β-catenin pathway has been shown to play an important role in the regulation of cell proliferation, differentiation and apoptosis (8-10). Lymphomas may show aberrant activation of the pathway (20), which therefore represents an attractive candidate for targeted therapeutic intervention in these tumors. More recently, a study investigated the apoptotic effects of ethacrynic acid (EA) and the antifungal agent ciclopirox olamine (CIC), another drug that inhibits Wnt/β-catenin signaling, on the myeloma cell line OPM-2 (23). EA is already used clinically as a diuretic agent. Glutathione-Stransferase (GST), which is overexpressed in human tumors in the form of GST-P, couples glutathione (GSH) with electrophilic compounds and detoxifies the cell (38). GSH acts as a reducing agent and antioxidant. The binding of EA to GSH can enhance the cytotoxicity of chemotherapeutic agents (39). CIC is used topically for the treatment of yeast infections in humans and is degraded by glucoronidation (40). It acts as a chelator of polyvalent metal cations (e.g. Fe3+ and Al3+), resulting in the inhibition of the metal-dependent enzymes in the metabolism of the cell. Furthermore, it blocks the cell cycle near the G1/S phase boundary (40).

Treatment of OPM-2 cells and the three lymphoma cell lines, OCI-LY8-LAM-53, SU-DHL-4 and Raji, led to a significant decrease of viability in these tumor cell lines but not in PBMCs derived from healthy donors (23). These results suggest a selective induction of apoptosis by CIC and EA in lymphoma and myeloma cells.

A recent study used a 96-well plate-based TOPflash reporter system to screen the Gen-plus drug library (Microsource, Gaylordsville, CT, USA), which contained 960 compounds (20). This screen identified EA and CIC as Wnt/β-catenin inhibitors. Given that the canonical Wnt signaling pathway is activated in lymphoma and myeloma cells (20), the study investigated whether EA and CIC may induce apoptosis and reduce the viability of lymphoma and myeloma cell lines. The effect of EA was studied in primary cultures derived from patients with chronic lymphocytic leukemia. Similar data as for cell lines were obtained for primary cells. The study showed a significant induction of apoptosis by CIC and EA in lymphoma and myeloma cells.

Taken together with previous results (20), these data suggested that EA and CIC can inhibit Wnt/β-catenin signaling in lymphoma and myeloma cell lines. In addition, EA was also shown to be effective in primary cultures derived from patients with chronic lymphocytic leukemia. These results are in accordance with a recent report (13) that the canonical Wnt signaling pathway is activated in MM through constitutively active β-catenin (23).

Aberrant activation of Wnt/β-catenin signaling promotes the development of several types of cancer. Recently, it was demonstrated that the Wnt pathway is also activated in lymphoma and myeloma (11, 13, 22, 23, 26). Therefore, the Wnt/β-catenin signaling molecules are attractive candidates for the development of targeted therapies in these diseases. To this extent, it was recently confirmed that the diuretic agent EA and the antifungal agent CIC inhibit Wnt/β-catenin signaling (20).

Patients with myeloma are currently treated with drugs such as doxorubicin and thalidomide or with novel compounds such as bortezomib and lenalidomide. Recently, these compounds were tested in combination with CIC and EA. CIC, lenalidomide and EA were more effective than thalidomide in decreasing the viability of myeloma cell lines. In addition, EA and CIC decreased the viability of lymphoma cells (20). In OPM-2 cells, the combination of CIC and EA plus bortezomib did not further decrease the viability of OPM cells. Interestingly, the addition of thalidomide and lenalidomide indicated a synergistic effect of these drugs with EA and CIC. Moreover, it was demonstrated that β-catenin expression is down-regulated when CIC and EA are added to lymphoma cells. These results revealed a significant selective induction of apoptosis by CIC and EA in both lymphoma and myeloma cells and suggested a synergistic effect when CIC and EA are combined with thalidomide or lenalidomide in myeloma cells. Interestingly, recently, similar results were obtained using drugs chemically similar to EA and CIC (41, 42).

In conclusion, the Wnt signaling pathway seems to be of major importance in myeloma. Influencing this pathway is a novel treatment strategy and should be investigated in further studies for future clinical use in patients with MM.