Chauhan Dharminder, Li Guilan, Podar Klaus, Hideshima Teru, Shringarpure Reshma, Catley Laurence, Mitsiades Constantine, Munshi Nikhil, Tai Yu Tzu, Suh Nanjoo, Gribble Gordon W, Honda Tadashi, Schlossman Robert, Richardson Paul, Sporn Michael B, Anderson Kenneth C
Jerome Lipper Multiple Myeloma Center, Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA.
Blood. 2004 Apr 15;103(8):3158-66. doi: 10.1182/blood-2003-08-2873. Epub 2003 Dec 11.
The synthetic triterpenoid 2-cyano-3, 12-dioxooleana-1, 9-dien-28-oic acid (CDDO) induces apoptosis in leukemic cells. Here we show that CDDO and its new derivative CDDO-imidazolide (CDDO-Im) trigger apoptosis in multiple myeloma (MM) cells resistant to conventional therapies including melphalan (LR-5), doxorubicin (Dox-40), and dexamethasone (MM.1R, U266, RPMI 8226) without affecting the viability of normal cells. CDDO-IM also triggers apoptosis in bone marrow stromal cells (BMSCs) and decreases interleukin-6 (IL-6) secretion induced by MM cell adhesion to BMSCs. Moreover, CDDO-Im-induced apoptosis in MM cells is not blocked by IL-6 or insulin growth factor-1 (IGF-1). Importantly, CDDO-Im and bortezomib/proteasome inhibitor PS-341 trigger synergistic apoptosis in MM cells associated with loss of mitochondrial membrane potential, superoxide generation, release of mitochondrial proteins cytochrome c/second mitochondria-derived activator of caspases (cytochrome c/Smac), and activation of caspase-8, -9, and -3. Conversely, the pancaspase inhibitor Z-VAD-fmk abrogates the CDDO-Im + bortezomib-induced apoptosis. Low doses of CDDO-Im and bortezomib overcome the cytoprotective effects of antiapoptotic proteins Bcl2 and heat shock protein-27 (Hsp27) as well as nuclear factor-kappa B (NF-kappaB)-mediated growth/survival and drug resistance. Finally, combining CDDO-Im and bortezomib induces apoptosis even in bortezomib-resistant MM patient cells. Together, these findings provide the framework for clinical evaluation of CDDO-Im, either alone or in combination with bortezomib, to overcome drug resistance and improve patient outcome in MM.
合成三萜类化合物2-氰基-3,12-二氧代齐墩果-1,9-二烯-28-酸（CDDO）可诱导白血病细胞凋亡。在此我们表明，CDDO及其新衍生物CDDO-咪唑化物（CDDO-Im）可在对包括美法仑（LR-5）、阿霉素（Dox-40）和地塞米松（MM.1R、U266、RPMI 8226）在内的传统疗法耐药的多发性骨髓瘤（MM）细胞中触发凋亡，而不影响正常细胞的活力。CDDO-IM还可触发骨髓基质细胞（BMSC）凋亡，并减少MM细胞黏附于BMSC所诱导的白细胞介素-6（IL-6）分泌。此外，IL-6或胰岛素生长因子-1（IGF-1）不会阻断CDDO-Im诱导的MM细胞凋亡。重要的是，CDDO-Im和硼替佐米/蛋白酶体抑制剂PS-341在MM细胞中触发协同凋亡，这与线粒体膜电位丧失、超氧化物生成、线粒体蛋白细胞色素c/第二线粒体衍生的半胱天冬酶激活剂（细胞色素c/Smac）释放以及半胱天冬酶-8、-9和-3激活有关。相反，泛半胱天冬酶抑制剂Z-VAD-fmk可消除CDDO-Im + 硼替佐米诱导的凋亡。低剂量的CDDO-Im和硼替佐米可克服抗凋亡蛋白Bcl2和热休克蛋白-27（Hsp27）以及核因子-κB（NF-κB）介导的生长/存活和耐药性的细胞保护作用。最后，联合使用CDDO-Im和硼替佐米即使在硼替佐米耐药的MM患者细胞中也能诱导凋亡。总之，这些发现为单独或与硼替佐米联合使用CDDO-Im进行临床评估提供了框架，以克服MM中的耐药性并改善患者预后。
