SDX‐308 and SDX‐101, Non‐Steroidal Anti‐Inflammatory Drugs, as Therapeutic Candidates for Treating Hematologic Malignancies Including Myeloma

Abstract

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.

Two novel aspirin analogues show selective cytotoxicity in primary chronic lymphocytic leukaemia cells that is associated with dual inhibition of Rel A and COX-2

“…As NF‐κB is also constitutively activated in CLL (31), it provides a potential rationale for over expression of COX‐2. Over the last decade, a number of studies have shown that NSAIDs may have efficacy in treatment of B‐cell malignancies including CLL (14,32–34). In this study, we report on pre‐clinical evaluation of two novel aspirin analogues, 2‐hydroxy benzoate zinc (2HBZ) and 4‐hydroxy benzoate zinc (4HBZ).…”

Enhancing Therapeutic Radiation Responses in Multiple Myeloma

“…Drugs like SC-58125 and SDX-101 without Cox-2 inhibitory activity induces cytotoxicity, overcomes drug resistance and enhances the activity of dexamethasone in MM (Feng et al, 2007a). SDX-308 (an indole-pyran analog of SDX-101) also shows anti-myeloma effect (Feng and Lentzsch, 2007;Lentzsch et al, 2007), inhibits RANKL-stimulated NF-κB activation and osteoclast formation (Feng et al, 2007a), and β-catenin/T-cell factor pathway (Feng and Lentzsch, 2007;Yasui et al, 2007). Sulindac also shows anti-myeloma effects by accumulation of p53, Bax, and Bak in mitochondria mediated by p38 MAPK activation downstream of ROS production (Seo et al, 2007).…”

“…Blood 109, 2130-2138. Feng, R., and Lentzsch, S. (2007). Treatment of multiple myeloma with SDX-308.…”

6‐Substituted Indolo[1,2‐c]quinazolines as New Antimicrobial Agents

“…Infact, indole derivatives are extremely important in chemistry, industry, and medicine. In the latter category, indole derivatives carrying different substituents are associated with a wide range of biological activities including anticancer [12 -14], anticonvulsant [15], antimicrobial [16 -18], antimalarial [19,20], antiprotozoal [21], anti-inflammatory [22,23], and antiHIV [24] properties. Moreover, fused indole derivatives such as indolocarbazoles [25,26], indoloisoquinolines [27,28], indoloquinoxalines [29,30], indoloquinazolines [31 -33] display a number of interesting pharmacological properties.…”