Griseofulvin Efficiently Induces Apoptosis in In Vitro Treatment of Lymphoma and Multiple Myeloma.

BACKGROUND/AIM: Recent innovations in the development of systemic and targeted therapies have improved survival and quality of life in multiple myeloma (MM) patients. However, in most cases, this hematological malignancy of monoclonal B-lymphocytes remains incurable. Exaggerated Wnt/ß-catenin signaling has been demonstrated in lymphoma and MM, therefore targeting related signaling molecules might represent a promising therapy approach. Griseofulvin, a widely used antifungal drug, is chemically related to other known Wnt-inhibitors and we recently demonstrated its potent in vivo efficacy in a murine myeloma model. MATERIALS AND METHODS: The anti-tumor apoptotic effect of griseofulvin at doses ranging from 0.1-200 µM was investigated on a total of ten human and two murine myeloma/lymphoma cell lines, as determined by 3'3-dihexyloxacarbocyanine iodide (DiOC6) and propidium iodide (PI) staining in flow cytometry. RESULTS: Griseofulvin significantly induced apoptosis in all investigated myeloma and lymphoma cell lines in a dose-dependent manner, while healthy control cells were less sensitive. CONCLUSION: Given the known safety profile and apoptosis induction at low effective doses, our data warrant further in vitro and in vivo studies utilizing griseofulvin as a potential therapy agent for MM and lymphoma.

In Vitro Efficacy of Naftifine Against Lymphoma and Multiple Myeloma.

BACKGROUND/AIM: Multiple myeloma is still an incurable hematological malignancy of monoclonal B-lymphocytes. While standard chemotherapy regimens have been used for years, novel agents like lenalidomide and bortezomib have become an essential part of today's therapies and significantly improve therapeutic efficacy. Nevertheless, new therapeutic strategies are still indispensable. Aberrant activation of Wnt/ß-catenin signaling promotes development of several cancers. Recently, it has been demonstrated that the Wnt pathway is activated in both lymphoma and myeloma. Thus, Wnt signaling molecules are attractive candidates for the development of new targeted-therapies. Naftifine was used in the present study since it has chemical features similar to those of other known WNT inhibitors. MATERIALS AND METHODS: The anti-tumor apoptotic effect of naftifine at doses ranging from 0.1-200 µM was investigated on two human and one murine lymphoma, as well as in one murine and three human myeloma cell lines, and determinded by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium-bromide (MTT) assay. RESULTS: Naftifine significantly reduced cell viability in all tested myeloma and lymphoma cell lines in a dose-dependent manner, while healthy cells were only slightly affected. CONCLUSION: Naftifine exhibits toxicity to hematological neoplasms in vitro.

Flunarizine exhibits in vitro efficacy against lymphoma and multiple myeloma cells.

BACKGROUND/AIM: Novel agents such as lenalidomide and bortezomib have significantly improved today's therapy of multiple myeloma. Despite recent innovations, new therapeutic options are needed. The Wingless-related integration site (WNT) pathway is aberrantly activated in lymphoma and myeloma and therefore renders WNT signaling molecules attractive for the development of targeted therapies. Flunarizine was used in this study as it has chemical features similar to those of other known WNT inhibitors and already proven proapoptotic properties in leukemia cells. MATERIALS AND METHODS: The antitumor apoptotic effect of flunarizine at doses ranging from 0.1-200 µM was investigated on three human lymphoma cell lines, one murine and four human myeloma cell lines by 3'3-Dihexyloxacarbocyanine iodide and propidium iodide staining in flow cytometry. RESULTS: Flunarizine induced significant apoptotic activity in all tested myeloma and lymphoma cell lines in a dose-dependent manner. CONCLUSION: Our results reveal a significant selective induction of apoptosis by flunarizine and suggest an in vivo effect against lymphoma and myeloma.

In vitro efficacy of cinnarizine against lymphoma and multiple myeloma.

BACKGROUND/AIM: Multiple myeloma, a well-known but still incurable disease, is a hematological malignancy of B-lymphocytes. While standard chemotherapy regimens have been used for years, novel agents, such as lenalidomide and bortezomib, have become an essential part of today's therapies. Nevertheless, new therapeutical strategies are required in the future. Aberrant activation of wingless-related integration site (WNT)/ß-catenin signaling promotes the development of several types of cancer. Recently, it has been demonstrated that the WNT pathway is also activated in lymphoma and myeloma. Thus, the WNT signaling molecules are attractive candidates for the development of targeted therapies. To this extent, we recently confirmed that the diuretic agent ethacrynic acid (EA) and the antifungal agent ciclopirox olamine (CIC) inhibit WNT signaling. Cinnarizine has similar chemical features to those of CIC. MATERIALS AND METHODS: Thus, in this study the antitumor effect of cinnarizine on myeloma and lymphoma cells was investigated by DiOC6 and propidium iodide (PI)-staining in flow cytometry. RESULTS: Cinnarizine triggered a significant apoptotic activity in all tested myeloma and lymphoma cell lines in a concentration-dependent manner. Interestingly, healthy cells were mainly unaffected. CONCLUSION: These results reveal a significant selective induction of apoptosis by cinnarizine that might result from an inhibition of WNT signaling and suggest an in vivo efficacy against lymphoma and myeloma.

Increased in vivo efficacy of lenalidomide by addition of piroctone olamine.

BACKGROUND: It was recently confirmed that the antifungal agent ciclopirox olamine inhibits Wnt/beta catenin signaling in myeloma. Piroctone olamine (PO) has very similar chemical features to ciclopirox olamine. MATERIALS AND METHODS: This study investigated the antitumor effect of PO in vitro and in vivo in a murine myeloma model. RESULTS: PO demonstrated a major apoptotic activity in various human and murine myeloma and lymphoma cell lines, as well as in human primary cells. In vivo, tumor growth, as well as overall survival, was significantly reduced in mice treated with PO as compared to untreated mice. Interestingly, concerning tumor growth and survival of the animals, a significant additive effect was seen by the combination of lenalidomide plus PO as compared to single application. CONCLUSION: These results reveal a significant selective induction of apoptosis by PO and suggest a significant in vivo effect against myeloma.

In vivo efficacy of griseofulvin against multiple myeloma.

We recently confirmed that ciclopirox olamine inhibits Wnt/beta catenin signalling in myeloma. Griseofulvin (GF) has similar chemical features as compared to ciclopirox olamine. In this study the anti-tumor effect of GF was investigated. GF demonstrated a major apoptotic activity in various human and murine myeloma and lymphoma cell lines as well as in human primary cells. In vivo, tumor growth as well as overall survival were significantly reduced in mice treated with GF as compared to untreated mice. In conclusion, our results reveal a significant selective induction of apoptosis by GF and suggest a significant in vivo effect against myeloma.