Synergistic antitumor activity of sorafenib and MG149 in hepatocellular carcinoma cells
2
조회
0
다운로드
1
인용
0
참고문헌
키워드
초록
Advanced hepatocellular carcinoma (HCC) is among the mostchallenging cancers to overcome, and there is a need for bettertherapeutic strategies. Among the different cancer drugs thathave been used in clinics, sorafenib is considered the standardfirst-line drug for advanced HCC. Here, to identify a chemicalcompound displaying a synergistic effect with sorafenib in HCC,we screened a focused chemical library and found that MG149,a histone acetyltransferase inhibitor targeting the MYST family,exhibited the most synergistic anticancer effect with sorafenibon HCC cells. The combination of sorafenib and MG149 exerteda synergistic anti-proliferation effect on HCC cells by inducingapoptotic cell death. We revealed that cotreatment with sorafeniband MG149 aggravated endoplasmic reticulum (ER) stressto promote the death of HCC cells rather than adaptive cellsurvival. In addition, combined treatment with sorafenib andMG149 significantly increased the intracellular levels of unfoldedproteins and reactive oxygen species, which upregulated ERstress. Collectively, these results suggest that MG149 has thepotential to improve the efficacy of sorafenib in advanced HCCvia the upregulation of cytotoxic ER stress.
Abstract
Advanced hepatocellular carcinoma (HCC) is among the mostchallenging cancers to overcome, and there is a need for bettertherapeutic strategies. Among the different cancer drugs thathave been used in clinics, sorafenib is considered the standardfirst-line drug for advanced HCC. Here, to identify a chemicalcompound displaying a synergistic effect with sorafenib in HCC,we screened a focused chemical library and found that MG149,a histone acetyltransferase inhibitor targeting the MYST family,exhibited the most synergistic anticancer effect with sorafenibon HCC cells. The combination of sorafenib and MG149 exerteda synergistic anti-proliferation effect on HCC cells by inducingapoptotic cell death. We revealed that cotreatment with sorafeniband MG149 aggravated endoplasmic reticulum (ER) stressto promote the death of HCC cells rather than adaptive cellsurvival. In addition, combined treatment with sorafenib andMG149 significantly increased the intracellular levels of unfoldedproteins and reactive oxygen species, which upregulated ERstress. Collectively, these results suggest that MG149 has thepotential to improve the efficacy of sorafenib in advanced HCCvia the upregulation of cytotoxic ER stress.
참고문헌 (38)
- Llovet JM, "Sorafenib in advanced hepatocellular carcinoma", N Engl J Med, 359, pp.378~390 (2008)
- Cheng AL, "Efficacy and safety of sorafenib in patients in the Asia-Pacific region with advanced hepatocellular carcinoma : a phase III randomised, double-blind, placebo-controlled trial", Lancet Oncol, 10, pp.25~34 (2009)
- Rimassa L, "Navigating the new landscape of second-line treatment in advanced hepatocellular carcinoma", Liver International, 40, pp.1800~1811 (2020)
- Xia S, "The microenvironmental and metabolic aspects of sorafenib resistance in hepatocellular carcinoma", EBioMedicine, 51, pp.102610~ (2020)
- Huang A, "Targeted therapy for hepatocellular carcinoma", Signal Transduct Target Ther, 5, pp.146~ (2020)
- Rahmani M, "The kinase inhibitor sorafenib induces cell death through a process involving induction of endoplasmic reticulum stress", Mol Cell Biol, 27, pp.5499~5513 (2007)
- Zhou T, "RACK1 modulates apoptosis induced by sorafenib in HCC cells by interfering with the IRE1", XBP1 axis, 2015, pp.33, 3006~3014
- Won JK, "Protein disulfide isomerase inhibition synergistically enhances the efficacy of sorafenib for hepatocellular carcinoma", Hepatology, 66, pp.855~868 (2017)
- Zhou B, "Melatonin increases the sensitivity of hepatocellular carcinoma to sorafenib through the PERK-ATF4-Beclin1 pathway", Int J Biol Sci, 15, pp.1905~1920 (2019)
- Hetz C, "The unfolded protein response and cell fate control", Mol Cell, 69, pp.169~181 (2018)
- Shimizu S, "Inhibition of autophagy potentiates the antitumor effect of the multikinase inhibitor sorafenib in hepatocellular carcinoma", Int J Cancer, 131, pp.548~557 (2012)
- Ma MKF, "Stearoyl-CoA desaturase regulates sorafenib resistance via modulation of ER stress-induced differentiation", J Hepatol, 67, pp.979~990 (2017)
- Tanaka K, "Targeting Aurora B kinase prevents and overcomes resistance to EGFR inhibitors in lung cancer by enhancing BIM-and PUMA-mediated apoptosis", Cancer Cell, 39, pp.1245~1261 (2021)
- Harris IS, "Deubiquitinases maintain protein homeostasis and survival of cancer cells upon glutathione depletion", Cell Metab, 29, pp.1166~1181 (2019)
- Broux M, "Suz12 inactivation cooperates with JAK3 mutant signaling in the development of T-cell acute lymphoblastic leukemia", Blood, 134, pp.1323~1336 (2019)
- Niles AL, "In vitro viability and cytotoxicity testing and same-well multi-parametric combinations for high throughput screening", Curr Chem Genomics, 3, pp.33~41 (2009)
- Sun Y, "Inhibition of histone acetyltransferase activity by anacardic acid sensitizes tumor cells to ionizing radiation", FEBS Lett, 580, pp.4353~4356 (2006)
- Ghizzoni M, "6-alkylsalicylates are selective Tip60 inhibitors and target the acetyl-CoA binding site", Eur J Med Chem, 47, pp.337~344 (2012)
- Balasubramanyam K, "Small molecule modulators of histone acetyltransferase p300", J Biol Chem, 278, pp.19134~19140 (2003)
- Kusakabe Y, "EZH1", 2inhibition augments the anti-tumor effects of sorafenib in hepatocellular carcinoma, 2021, pp.11, 21396~
- Green AS, "Pim kinases modulate resistance to FLT3 tyrosine kinase inhibitors in FLT3-ITD acute myeloid leukemia", Sci Adv, 1, pp.e1500221~ (2015)
- Yu H, "Prospective pharmacological methodology for establishing and evaluating anti-cancer drug resistant cell lines", BMC Cancer, 21, pp.1049~ (2021)
- Chou TC, "Drug combination studies and their synergy quantification using the Chou-Talalay Method", Cancer Res, 70, pp.440~446 (2010)
- Oslowski CM, "Measuring ER stress and the unfolded protein response using mammalian tissue culture system", Methods Enzymol, 490, pp.71~92 (2011)
- Chi-Ho Lee, "Metformin ameliorates bile duct ligation-induced acute hepatic injury via regulation of ER stress", BMB Reports, 53(6), pp.311~316 (2020), 생화학분자생물학회[DOI]
- Oyadomari S, "Roles of CHOP", GADD153in endoplasmic reticulum stress, 2004, pp.11, 381~389
- Novoa I, "Feedback inhibition of the unfolded protein response by GADD34-mediated dephosphorylation of eIF2alpha", J Cell Biol, 153, pp.1011~1022 (2001)
- Ogata M, "Autophagy is activated for cell survival after endoplasmic reticulum stress", Mol Cell Biol, 26, pp.9220~9231 (2006)
- Hetz C, "Proteostasis control by the unfolded protein response", Nat Cell Biol, 17, pp.829~838 (2015)
- Soohyun Lee, "Mitochondrial dysfunction induced by callyspongiolide promotes autophagy-dependent cell death", BMB Reports, 54(4), pp.227~232 (2021), 생화학분자생물학회
- Kaizuka T, "An autophagic flux probe that releases an internal control", Mol Cell, 64, pp.835~849 (2016)
- Shen D, "Novel cell-and tissue-based assays for detecting misfolded and aggregated protein accumulation within aggresomes and inclusion bodies", Cell Biochem Biophys, 60, pp.173~185 (2011)
- Wang C, "Human protein-disulfide isomerase is a redoxregulated Chaperone activated by oxidation of domain a’", J Biol Chem, 287, pp.1139~1149 (2012)
- Coriat R, "Sorafenib-induced hepatocellular carcinoma cell death depends on reactive oxygen species production in vitro and in vivo", Mol Cancer Ther, 11, pp.2284~2293 (2012)
- Song Y, "Patient-derived multicellular tumor spheroids towards optimized treatment for patients with hepatocellular carcinoma", J Exp Clin Cancer Res, 37, pp.109~ (2018)
- Corazzari M, "Endoplasmic reticulum stress, unfolded protein response, and cancer cell fate", Front Oncol, 7, pp.78~ (2017)
- Yongkang Zou, "Implications of telomerase reverse transcriptase in tumor metastasis", BMB Reports, 53(9), pp.458~465 (2020), 생화학분자생물학회[DOI]
- Lin A, "Off-target toxicity is a common mechanism of action of cancer drugs undergoing clinical trials", Sci Transl Med, 11, pp.eaaw8412~ (2019)