sdx-308 and Multiple-Myeloma

Non-steroidal anti-inflammatory drugs have been shown to inhibit carcinogenesis in colon cancer, and to induce apoptosis in a variety of tumor cell lines. Some anti-tumor effects are thought to be related to their cyclooxygenase-2-inhibitory activity, but recent studies have shown that non-steroidal anti-inflammatory drugs exert their anti-tumor effect via cyclooxygenase-2-independent mechanism. SDX-308 (CEP-18082) is a non-cyclooxygenase-2-inhibiting indole-pyran analog and is structurally related to SDX-101, an R-enantiomer of etodolac. SDX-308 has a potent anti-myeloma effect and shows synergism in combination with other drugs for the treatment of chronic lymphocytic leukemia. In addition SDX-308 inhibits osteoclast formation and activity and thereby might be an attractive drug for the treatment of diseases with increased osteoclast activity such as osteolytic lesions in multiple myeloma and metastatic carcinomas, as well as osteoporosis. This review covers future application of SDX-308 as an anti-myeloma drug regulating increased osteoclast activity.

Topics: Anti-Inflammatory Agents, Non-Steroidal; Antineoplastic Agents; Etodolac; Hematologic Neoplasms; Heterocyclic Compounds, 3-Ring; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Multiple Myeloma; NF-kappa B; Osteoclasts; Stereoisomerism

Multiple myeloma (MM) is a hematologic malignancy characterized by dysregulated proliferation of plasma cells and increased osteoclast activity that results in bone destruction and lytic lesions. Therefore, novel treatment modalities targeting both myeloma cell and osteoclast function may dramatically improve MM patient outcome. As an R-enantiomer of the cyclooxygenase (COX) inhibitor etodolac, SDX-101 has shown favorable antimyeloma effects. More recently, another structural analogue of etodolac, SDX-308, has displayed in vitro cytotoxic activity on tumor lines and in vivo antitumor efficacy in mice. SDX-308 has high antimyeloma activity and shows synergism in combination with other drugs for the treatment of chronic lymphocytic leukemia (CLL). In addition SDX-308 inhibits osteoclast (OCL) formation resulting in complete abrogation of bone resorption. Therefore, SDX-308 might be an attractive drug for the treatment of diseases with increased OCL activity, such as osteolytic lesions in multiple myeloma and metastatic carcinomas as well as osteoporosis. In the present review, we discuss SDX-308 as a new therapeutic candidate for the treatment of MM and diseases with increased osteoclast activity.

Topics: Anti-Inflammatory Agents, Non-Steroidal; Antineoplastic Agents; Bone Diseases; Drug Therapy; Etodolac; Heterocyclic Compounds, 3-Ring; Humans; Multiple Myeloma; Osteoclasts; Tumor Necrosis Factor-alpha

Multiple myeloma is characterized by increased osteoclast activity that results in bone destruction and lytic lesions. With the prolonged overall patient survival achieved by new treatment modalities, additional drugs are required to inhibit bone destruction. We focused on a novel and more potent structural analog of the nonsteroidal anti-inflammatory drug etodolac, known as SDX-308, and its effects on osteoclastogenesis and multiple myeloma cells. SDX-101 is another structural analog of etodolac that is already used in clinical trials for the treatment of B-cell chronic lymphocytic leukemia (B-CLL). Compared with SDX-101, a 10-fold lower concentration of SDX-308 induced potent (60%-80%) inhibition of osteoclast formation, and a 10- to 100-fold lower concentration inhibited multiple myeloma cell proliferation. Bone resorption was completely inhibited by SDX-308, as determined in dentin-based bone resorption assays. SDX-308 decreased constitutive and RANKL-stimulated NF-kappaB activation and osteoclast formation in an osteoclast cellular model, RAW 264.7. SDX-308 effectively suppressed TNF-alpha-induced IKK-gamma and IkappaB-alpha phosphorylation and degradation and subsequent NF-kappaB activation in human multiple myeloma cells. These results indicate that SDX-308 effectively inhibits multiple myeloma cell proliferation and osteoclast activity, potentially by controlling NF-kappaB activation signaling. We propose that SDX-308 is a promising therapeutic candidate to inhibit multiple myeloma growth and osteoclast activity and that it should receive attention for further study.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Bone Resorption; Cell Differentiation; Cell Proliferation; Heterocyclic Compounds, 3-Ring; Humans; Mice; Multiple Myeloma; NF-kappa B; Osteoblasts; Osteoclasts; RANK Ligand; Signal Transduction; Tumor Cells, Cultured

We have reported previously that R-enantiomer of etodolac (R-etodolac), which is under investigation in phase 2 clinical trials in chronic lymphocytic leukemia, induces potent cytotoxicity at clinically relevant concentrations in multiple myeloma (MM) cells. In this study, we demonstrated that SDX-308 (CEP-18082), a novel analog of etodolac, has more potent cytotoxicity than R-etodolac against both MM cell lines and patient MM cells, including tumor cells resistant to conventional (dexamethasone, doxorubicine, melphalan) and novel (bortezomib) therapies. SDX-308-induced cytotoxicity is triggered by caspase-8/9/3 activation and poly (ADP-ribose) polymerase cleavage, followed by apoptosis. SDX-308 significantly inhibits beta-catenin/T-cell factor pathway by inhibiting nuclear translocation of beta-catenin, thereby downregulating transcription and expression of downstream target proteins including myc and survivin. Neither interleukin-6 nor insulin-like growth factor-1 protect against growth inhibition triggered by SDX-308. Importantly, growth of MM cells adherent to bone marrow (BM) stromal cells is also significantly inhibited by SDX-308. Our data therefore indicate that the novel etodolac analog SDX-308 can target MM cells in the BM milieu.

Topics: Antineoplastic Agents; Apoptosis; beta Catenin; Cell Line, Tumor; Cysteine Proteinase Inhibitors; Drug Resistance, Neoplasm; Drug Screening Assays, Antitumor; Etodolac; Gene Expression Regulation, Neoplastic; Heterocyclic Compounds, 3-Ring; Humans; Insulin-Like Growth Factor I; Interleukin-6; Multiple Myeloma; Neoplasm Proteins; Poly(ADP-ribose) Polymerases; Signal Transduction; TCF Transcription Factors