| Reference | 1. J Exp Clin Cancer Res. 2016 Sep 30;35(1):158.<br />
LCL161 increases paclitaxel-induced apoptosis by degrading cIAP1 and cIAP2 in NSCLC.<br />
Yang C(1), Wang H(2)(3), Zhang B(2), Chen Y(1), Zhang Y(1), Sun X(2), Xiao G(2), Nan K(1), Ren H(4), Qin S(5).<br />
Author information:<br />
(1)Department of Oncology, The First Affiliated Hospital of Xi/'an Jiaotong University, 277 West Yanta Road, Xi/'an, Shaanxi, 710061, China. (2)Department Two of Thoracic Surgery, The First Affiliated Hospital of Xi/'an Jiaotong University, 277 West Yanta Road, Xi/'an, Shaanxi, 710061, China. (3)Department of Surgical Oncology, Baoji Central Hospital, Baoji, Shaanxi, 721008, China. (4)Department Two of Thoracic Surgery, The First Affiliated Hospital of Xi/'an Jiaotong University, 277 West Yanta Road, Xi/'an, Shaanxi, 710061, China. [email protected]. (5)Department Two of Thoracic Surgery, The First Affiliated Hospital of Xi/'an Jiaotong University, 277 West Yanta Road, Xi/'an, Shaanxi, 710061, China. [email protected].<br />
BACKGROUND: LCL161, a novel Smac mimetic, is known to have anti-tumor activity and improve chemosensitivity in various cancers. However, the function and mechanisms of the combination of LCL161 and paclitaxel in non-small cell lung cancer (NSCLC) remain unknown.<br />
METHODS: Cellular inhibitor of apoptotic protein 1 and 2 (cIAP1&2) expression in NSCLC tissues and adjacent non-tumor tissues were assessed by immunohistochemistry. The correlations between cIAP1&2 expression and clinicopathological characteristics, prognosis were analyzed. Cell viability and apoptosis were measured by MTT assays and Flow cytometry. Western blot and co-immunoprecipitation assay were performed to measure the protein expression and interaction in NF-kB pathway. siRNA-mediated gene silencing and caspases activity assays were applied to demonstrate the role and mechanisms of cIAP1&2 and RIP1 in lung cancer cell apoptosis. Mouse xenograft NSCLC models were used in vivo to determine the therapeutic efficacy of LCL161 alone or in combination with paclitaxel.<br />
RESULTS: The expression of cIAP1 and cIAP2 in Non-small cell lung cancer (NSCLC) tumors was significantly higher than that in adjacent normal tissues. cIAP1 was highly expressed in patients with late TNM stage NSCLC and a poor prognosis. Positivity for both cIAP1 and cIAP2 was an independent prognostic factor that indicated a poorer prognosis in NSCLC patients. LCL161, an IAP inhibitor, cooperated with paclitaxel to reduce cell viability and induce apoptosis in NSCLC cells. Molecular studies revealed that paclitaxel increased TNFα expression, thereby leading to the recruitment of various factors and the formation of the TRADD-TRAF2-RIP1-cIAP complex. LCL161 degraded cIAP1&2 and released RIP1 from the complex. Subsequently, RIP1 was stabilized and bound to caspase-8 and FADD, thereby forming the caspase-8/RIP1/FADD complex, which activated caspase-8, caspase-3 and ultimately lead to apoptosis. In nude mouse xenograft experiments, the combination of LCL161 and paclitaxel degraded cIAP1,2, activated caspase-3 and inhibited tumor growth with few toxic effects.<br />
CONCLUSION: Thus, LCL161 could be a useful agent for the treatment of NSCLC in combination with paclitaxel.<br />
2. Oncotarget. 2016 Aug 30;7(35):56253-56265. doi: 10.18632/oncotarget.11028.<br />
Smac mimetic LCL161 overcomes protective ER stress induced by obatoclax, synergistically causing cell death in multiple myeloma.<br />
Ramakrishnan V(1), Gomez M(1), Prasad V(1), Kimlinger T(1), Painuly U(1)(2), Mukhopadhyay B(1), Haug J(1), Bi L(1)(3), Rajkumar SV(1), Kumar S(1).<br />
Author information:<br />
(1)Division of Hematology, Mayo Clinic, Rochester, MN, USA. (2)4th Department of Internal Medicine-Hematology, University Hospital Hradec Kralove and Charles University in Prague, Faculty of Medicine in Hradec Kralove, Czech Republic. (3)The Department of Hematology and Oncology, China-Japan Union Hospital, Jilin University, Changchun, Jilin, China.<br />
Bcl2 and IAP families are anti-apoptotic proteins deregulated in multiple myeloma (MM) cells. Pharmacological inhibition of each of these families has shown significant activity only in subgroups of MM patients. Here, we have examined a broad-spectrum Bcl2 family inhibitor Obatoclax (OBX) in combination with a Smac mimetic LCL161 in MM cell lines and patient cells. LCL161/OBX combination induced synergistic cytotoxicity and anti-proliferative effects on a broad range of human MM cell lines. The cytotoxicity was mediated through inhibition of the IAPs, activation of caspases and up regulation of the pro-apoptotic proteins Bid, Bim, Puma and Noxa by the drug combination. In addition, we observed that OBX caused ER stress and activated the Unfolded Protein Response (UPR) leading to drug resistance. LCL161, however inhibited spliced Xbp-1, a pro-survival factor. In addition, we observed that OBX increased GRP78 localization to the cell surface, which then induced PI3K dependent Akt activation and resistance to cell death. LCL161 was able to block OBX induced Akt activation contributing to synergistic cell death. Our results support clinical evaluation of this combination strategy in relapsed refractory MM patients.<br />
3. Biochem Pharmacol. 2012 Aug 1;84(3):268-77. doi: 10.1016/j.bcp.2012.04.023. Epub 2012 May 9.<br />
Inhibition of Bcl-2 improves effect of LCL161, a SMAC mimetic, in hepatocellular carcinoma cells.<br />
Chen KF(1), Lin JP, Shiau CW, Tai WT, Liu CY, Yu HC, Chen PJ, Cheng AL.<br />
Author information:<br />
(1)Department of Medical Research, National Taiwan University Hospital, Taipei, Taiwan. [email protected]<br />
In this study, we investigated the effect of LCL161, a SMAC mimetic, in hepatocellular carcinoma (HCC). LCL161 showed differential effects on apoptosis in four HCC cell lines, and the endogenous level of Bcl-2 determined the sensitivity of HCC cells to LCL161. Cytotoxicity and apoptosis were observed in sensitive PLC5 and Hep3B cells that express lower levels of Bcl-2, but not in resistant Huh-7 and SK-Hep1 cells with higher Bcl-2 expression. Down regulation of Bcl-2 by small interference RNA overcame the resistance to LCL161 in Huh-7, and the apoptotic effect was rescued in Bcl-2-expressing Hep3B. To test the hypothesis that Bcl-2 determines the sensitivity of HCC cells to LCL161, we assayed the biological effect of SC-2001, a novel Bcl-2 inhibitor derived from obatoclax, in LCL161-resistant cell lines. Huh-7 cells co-treated with LCL161 and SC-2001 showed a significant dose-dependent apoptotic effect demonstrated by sub-G1 assay and cleavage of PARP. Furthermore, the combination index (CI) of LCL161 and SC-2001 showed a convincing synergism in resistant Huh-7. In addition, the combinational therapy showed significant growth inhibition in Huh-7-bearing xenograft tumors. Notably, down regulation of Bcl-2 was observed in a tumor sample treated with LCL161 and SC-2001. In conclusion, targeting Bcl-2 with SC-2001 overcomes drug resistance to LCL161 in HCC cells thus suggesting a new anti-IAP combinational therapy for HCC.<br />
4. Pediatr Blood Cancer. 2012 Apr;58(4):636-9. doi: 10.1002/pbc.23167. Epub 2011 Jun 16.<br />
Initial testing (stage 1) of LCL161, a SMAC mimetic, by the Pediatric Preclinical Testing Program.<br />
Houghton PJ(1), Kang MH, Reynolds CP, Morton CL, Kolb EA, Gorlick R, Keir ST, Carol H, Lock R, Maris JM, Billups CA, Smith MA.<br />
Author information:<br />
(1)Nationwide Children/'s Hospital, Columbus, Ohio 43205, USA. [email protected]<br />
LCL161, a SMAC mimetic, was tested against the PPTP in vitro panel (1.0 nM to 10.0 μM) and the PPTP in vivo panels (30 or 75 mg/kg [solid tumors] or 100 mg/kg [ALL]) administered orally twice in a week. LCL161 showed a median relative IC(50) value of >10 μM, being more potent against several leukemia and lymphoma lines. In vivo LCL161 induced significant differences in EFS distribution in approximately one-third of solid tumor xenografts (osteosarcoma and glioblastoma), but not in ALL xenografts. No objective tumor responses were observed. In vivo LCL161 demonstrated limited single agent activity against the pediatric preclinical models studied.<br />
|
