3-3--dihexyl-2-2--oxacarbocyanine and Multiple-Myeloma

Recent innovations in the treatment of multiple myeloma have enriched our therapeutic repertoire regarding the treatment of multiple myeloma during the last decades. However, despite today's therapies many multiple myeloma (MM) patients experience relapse of disease and eventually remain incurable. Wnt/β-catenin signaling has been demonstrated in lymphoma and MM, rendering related signaling molecules promising therapeutic targets. Fenofibrate, an extensively scrutinized and widely used drug for primary hypercholesterolemia or mixed dyslipidemia, has proven anticarcinogenic properties mediated by peroxisome proliferator-activated receptor-alpha (PPARα) agonism, thereby also influencing WNT-associated signaling molecules.. The antitumor apoptotic effect of fenofibrate at doses ranging from 0.1-200 μM was investigated on a total of seven human, two murine myeloma/lymphoma cell lines and two healthy control cell lines, as determined by 3'3-Dihexyloxacarbocyanine iodide (DiOC6) and propidium iodide (PI) staining in flow cytometry.. Fenofibrate significantly reduced viability due to apoptosis induction in all investigated myeloma and lymphoma cell lines in a dose-dependent manner, whereas healthy control cells were less sensitive.. Our results provide a rationale for future in vitro and in vivo studies with fenofibrate as a safe and well-tolerated agent in MM and lymphoma treatment.

Topics: Anticarcinogenic Agents; Apoptosis; beta Catenin; Carbocyanines; Cell Line, Tumor; Fenofibrate; Humans; Lymphoma; Multiple Myeloma; Staining and Labeling; Wnt Signaling Pathway

Bruceantin has been shown to induce cell differentiation in a number of leukemia and lymphoma cell lines. It also down-regulated c-MYC, suggesting a correlation of down-regulation with induction of cell differentiation or cell death. In the present study, we focused on multiple myeloma, using the RPMI 8226 cell line as a model.. The effects of bruceantin on c-MYC levels and apoptosis were examined by immunoblotting, 4',6-diamidino-2-phenylindole staining, evaluation of caspase-like activity, and 3,3'-dihexyloxacarbocyanine iodide staining. The potential of bruceantin to inhibit primary tumor growth was assessed with RPMI 8226 xenografts in SCID mice, and apoptosis in the tumors was evaluated by the terminal deoxynucleotidyl transferase-mediated nick end labeling assay.. c-MYC was strongly down-regulated in cultured RPMI 8226 cells by treatment with bruceantin for 24 h. With U266 and H929 cells, bruceantin did not regulate c-MYC in this manner. Apoptosis was induced in the three cell lines. In RPMI 8226 cells, apoptosis occurred through proteolytic processing of procaspases and degradation of poly(ADP-ribose) polymerase. The mitochondrial pathway was also involved. Because RPMI 8226 cells were the most sensitive, they were used in a xenograft model. Bruceantin treatment (2.5-5 mg/kg) resulted in a significant regression of tumors without overt toxicity. Apoptosis was significantly elevated in tumors derived from animals treated with bruceantin (37%) as compared with the control tumors (14%).. Bruceantin interferes with the growth of RPMI 8226 cells in cell culture and xenograft models. These results suggest that bruceantin should be reinvestigated for clinical efficacy against multiple myeloma and other hematological malignancies.

Topics: Animals; Apoptosis; BH3 Interacting Domain Death Agonist Protein; Carbocyanines; Carrier Proteins; Caspase 3; Caspase 7; Caspase 8; Caspase 9; Caspases; Cell Differentiation; Cell Line, Tumor; Dose-Response Relationship, Drug; Down-Regulation; Enzyme Activation; Fluorescent Dyes; Humans; Immunoblotting; Immunohistochemistry; In Situ Nick-End Labeling; Membrane Potentials; Mice; Mice, SCID; Mitochondria; Models, Chemical; Multiple Myeloma; Neoplasm Transplantation; Poly(ADP-ribose) Polymerases; Propidium; Proto-Oncogene Proteins c-myc; Quassins