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Yasui, Hiroshi; Hideshima, Teru; Neri, Paola; Jin, Janice; Kiziltepe, Tanyel; Shiraishi, Norihiko; Ishitsuka, Kenji; Laurence, Catley P.; Raje, Noopur; Podar, Klaus; Tassone, Pierfrancesco; Chauhan, Dharminder; Richardson, Paul G.; Leoni, Lorenzo M.; Kanekal, Sarath; Elliott, Gary T.; Munshi, Nikhil C.; Anderson, Kenneth C.

R-Etodolac and a Novel Indole-Pyran Structural Analog, SDX-308, Induce Cytotoxicity and Overcome Drug Resistance in Multiple Myeloma

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  • Media type: E-Article
  • Title: R-Etodolac and a Novel Indole-Pyran Structural Analog, SDX-308, Induce Cytotoxicity and Overcome Drug Resistance in Multiple Myeloma
  • Contributor: Yasui, Hiroshi; Hideshima, Teru; Neri, Paola; Jin, Janice; Kiziltepe, Tanyel; Shiraishi, Norihiko; Ishitsuka, Kenji; Laurence, Catley P.; Raje, Noopur; Podar, Klaus; Tassone, Pierfrancesco; Chauhan, Dharminder; Richardson, Paul G.; Leoni, Lorenzo M.; Kanekal, Sarath; Elliott, Gary T.; Munshi, Nikhil C.; Anderson, Kenneth C.
  • imprint: American Society of Hematology, 2005
  • Published in: Blood
  • Language: English
  • DOI: 10.1182/blood.v106.11.1580.1580
  • ISSN: 0006-4971; 1528-0020
  • Keywords: Cell Biology ; Hematology ; Immunology ; Biochemistry
  • Origination:
  • Footnote:
  • Description: <jats:title>Abstract</jats:title> <jats:p>SDX-101, the less toxic R-isomer of the commercially available non-steroidal inflammatory drug R,S-etodolac (Lodine®), lacks COX inhibitory activity and is being investigated in Phase II clinical trials in chronic lymphocytic leukemia. Recently, we reported that R-etodolac, at clinically relevant concentrations, induces potent in vitro cytotoxicity in drug-sensitive and conventional drug-resistant multiple myeloma (MM) cell lines, as well as in primary tumor cells from MM patients. R-etodolac triggers caspase/poly-ADP-ribose polymerase (PARP) cleavage and downregulates of cyclin D1 expression (Yasui et al. Blood 2005). Importantly, R-etodolac at sub-cytotoxic doses upregulates Mcl-1s and synergistically enhances dexamethasone (Dex)-induced caspase-dependent apoptosis in Dex-sensitive MM.1S cells. Combination of R-etodolac with Dex enhances cytotoxicity in Dex resistant OPM1 MM cells and in Dex-resistant patient MM cells in vitro. We further studied the in vivo anti-tumor effect of combined R-etodolac and Dex in SCID mice injected subcutaneously with OPM1 human MM cells. While oral treatment of SCID mice with R-etodolac alone (250 mg/kg/d) or Dex alone (1 mg/kg/d) did not induce any significant reduction of tumor volume compared with control (PBS), the combination of R-etodolac and Dex inhibited tumor growth synergistically (synergism quotient = 1.6) and significantly (p = 0.023), suggesting that R-etodolac may reverse Dex resistance in MM. Finally, we demonstrated that racemic SDX-308, a novel indole-pyran structural analog of etodolac, has 10-fold more potent cytotoxicity than R-etodolac in MM cell lines both sensitive and resistant to conventional therapies, as well as in patient’s MM cells. Moreover, SDX-308, like R-etodolac, can overcome the viability and proliferative enhancing effects of exogeneous IL-6, IGF-1, or bone marrow stroma cells. These combined observations indicate that SDX-308 is a promising more potent second generation analog of R-etodolac for MM therapy. Our data suggest that R-etodolac and its novel analog SDX-308 overcome resistance to some conventional therapeutics used for MM, and provide preclinical rationale to conduct clinical trials of R-etodolac and SDX-308 to treat MM.</jats:p>
  • Access State: Open Access