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Molecule Details

General Information of the Molecule
Name
Bcl-2-like protein 3 (MCL1)
Synonyms
Induced myeloid leukemia cell differentiation protein Mcl-1; mcl1/EAT; Bcl2-L-3; Bcl-2-related protein EAT/mcl1; Bcl-2-like protein 3; BCL2L3
Gene Name
MCL1
Gene ID
4170
Sequence
MFGLKRNAVIGLNLYCGGAGLGAGSGGATRPGGRLLATEKEASARREIGGGEAGAVIGGS
AGASPPSTLTPDSRRVARPPPIGAEVPDVTATPARLLFFAPTRRAAPLEEMEAPAADAIM
SPEEELDGYEPEPLGKRPAVLPLLELVGESGNNTSTDGSLPSTPPPAEEEEDELYRQSLE
IISRYLREQATGAKDTKPMGRSGATSRKALETLRRVGDGVQRNHETAFQGMLRKLDIKNE
DDVKSLSRVMIHVFSDGVTNWGRIVTLISFGAFVAKHLKTINQESCIEPLAESITDVLVR
TKRDWLVKQRGWDGFVEFFHVEDLEGGIRNVLLAFAGVAGVGAGLAYLIR
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Function
Mediates its effects by interactions with a number of other regulators of apoptosis. Isoform 1 inhibits apoptosis. Isoform 2 promotes apoptosis. Involved in the regulation of apoptosis versus cell survival, and in the maintenance of viability but not of proliferation.
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Uniprot ID
MCL1_HUMAN
Pfam
PF00452
KEGG ID
hsa4170
TTD ID
T14912
A List of Drug Combination(s) Able to Regulate This Molecule
          Expression Regulation     Click to Show/Hide the Drug Combination Regulating This Molecule
                 Down-regulation     Click to Show/Hide
                    Drug Combination 1 Down-regulating the Expression of This Molecule [1]
                    Detail(s)  Combination Info  click to show the detail info of this combination
                    Name Dicoumarol   NP Info  + Cisplatin   Drug Info 
                    Structure +
                    Drug Combination 2 Down-regulating the Expression of This Molecule [2]
                    Detail(s)  Combination Info  click to show the detail info of this combination
                    Name Triptolide   NP Info  + Vasostatin   Drug Info 
                    Structure +
                    Drug Combination 3 Down-regulating the Expression of This Molecule [3]
                    Detail(s)  Combination Info  click to show the detail info of this combination
                    Name Triptolide   NP Info  + Gemcitabine   Drug Info 
                    Structure +
                    Drug Combination 4 Down-regulating the Expression of This Molecule [4]
                    Detail(s)  Combination Info  click to show the detail info of this combination
                    Name Fisetin   NP Info  + Sorafenib   Drug Info 
                    Structure +
                    Drug Combination 5 Down-regulating the Expression of This Molecule [5]
                    Detail(s)  Combination Info  click to show the detail info of this combination
                    Name Shikonin   NP Info  + TNF-related apoptosis inducing ligand    Drug Info 
                    Structure +
                    Drug Combination 6 Down-regulating the Expression of This Molecule [6]
                    Detail(s)  Combination Info  click to show the detail info of this combination
                    Name Triptolide   NP Info  + Venetoclax   Drug Info 
                    Structure +
                    Drug Combination 7 Down-regulating the Expression of This Molecule [7]
                    Detail(s)  Combination Info  click to show the detail info of this combination
                    Name Apigenin   NP Info  + 5-fluorouracil   Drug Info 
                    Structure +
                    Drug Combination 8 Down-regulating the Expression of This Molecule [8]
                    Detail(s)  Combination Info  click to show the detail info of this combination
                    Name Paclitaxel   NP Info  + ABT-737   Drug Info 
                    Structure +
                    Drug Combination 9 Down-regulating the Expression of This Molecule [9]
                    Detail(s)  Combination Info  click to show the detail info of this combination
                    Name Apigenin   NP Info  + ABT-263   Drug Info 
                    Structure +
                    Drug Combination 10 Down-regulating the Expression of This Molecule [10]
                    Detail(s)  Combination Info  click to show the detail info of this combination
                    Name Magnolol   NP Info  + TNF-related apoptosis inducing ligand    Drug Info 
                    Structure +
                    Drug Combination 11 Down-regulating the Expression of This Molecule [11]
                    Detail(s)  Combination Info  click to show the detail info of this combination
                    Name Bufalin   NP Info  + Osimertinib   Drug Info 
                    Structure +
                    Drug Combination 12 Down-regulating the Expression of This Molecule [12]
                    Detail(s)  Combination Info  click to show the detail info of this combination
                    Name Gossypol   NP Info  + Imatinib   Drug Info 
                    Structure +
                    Drug Combination 13 Down-regulating the Expression of This Molecule [13]
                    Detail(s)  Combination Info  click to show the detail info of this combination
                    Name Triptolide   NP Info  + Cisplatin   Drug Info 
                    Structure +
                    Drug Combination 14 Down-regulating the Expression of This Molecule [14]
                    Detail(s)  Combination Info  click to show the detail info of this combination
                    Name Vitamin K2   NP Info  + Sorafenib   Drug Info 
                    Structure +
                    Drug Combination 15 Down-regulating the Expression of This Molecule [15]
                    Detail(s)  Combination Info  click to show the detail info of this combination
                    Name Arsenic trioxide   NP Info  + ABT-737   Drug Info 
                    Structure +
                    Drug Combination 16 Down-regulating the Expression of This Molecule [16]
                    Detail(s)  Combination Info  click to show the detail info of this combination
                    Name Honokiol   NP Info  + Osimertinib   Drug Info 
                    Structure +
                    Drug Combination 17 Down-regulating the Expression of This Molecule [17]
                    Detail(s)  Combination Info  click to show the detail info of this combination
                    Name Vincristine   NP Info  + Belinostat   Drug Info 
                    Structure +
                    Drug Combination 18 Down-regulating the Expression of This Molecule [18]
                    Detail(s)  Combination Info  click to show the detail info of this combination
                    Name Bufalin   NP Info  + 5-fluorouracil   Drug Info 
                    Structure +
                    Drug Combination 19 Down-regulating the Expression of This Molecule [19]
                    Detail(s)  Combination Info  click to show the detail info of this combination
                    Name Bufalin   NP Info  + TNF-related apoptosis inducing ligand    Drug Info 
                    Structure +
                    Drug Combination 20 Down-regulating the Expression of This Molecule [20]
                    Detail(s)  Combination Info  click to show the detail info of this combination
                    Name Silibinin   NP Info  + Vorinostat   Drug Info 
                    Structure +
                    Drug Combination 21 Down-regulating the Expression of This Molecule [21]
                    Detail(s)  Combination Info  click to show the detail info of this combination
                    Name Flavopiridol   NP Info  + Venetoclax   Drug Info 
                    Structure +
                    Drug Combination 22 Down-regulating the Expression of This Molecule [22]
                    Detail(s)  Combination Info  click to show the detail info of this combination
                    Name Curcumin   NP Info  + Thioridazine   Drug Info 
                    Structure +
                    Drug Combination 23 Down-regulating the Expression of This Molecule [23]
                    Detail(s)  Combination Info  click to show the detail info of this combination
                    Name Silibinin   NP Info  + Sorafenib   Drug Info 
                    Structure +
                    Drug Combination 24 Down-regulating the Expression of This Molecule [24]
                    Detail(s)  Combination Info  click to show the detail info of this combination
                    Name Vernodalol   NP Info  + TNF-related apoptosis inducing ligand    Drug Info 
                    Structure +
                    Drug Combination 25 Down-regulating the Expression of This Molecule [25]
                    Detail(s)  Combination Info  click to show the detail info of this combination
                    Name Gambogic acid   NP Info  + Imatinib   Drug Info 
                    Structure +
                    Drug Combination 26 Down-regulating the Expression of This Molecule [26]
                    Detail(s)  Combination Info  click to show the detail info of this combination
                    Name Betulinic Acid   NP Info  + TNF-related apoptosis inducing ligand    Drug Info 
                    Structure +
                    Drug Combination 27 Down-regulating the Expression of This Molecule [27]
                    Detail(s)  Combination Info  click to show the detail info of this combination
                    Name Daunorubicin   NP Info  + PP242   Drug Info 
                    Structure +
                    Drug Combination 28 Down-regulating the Expression of This Molecule [28]
                    Detail(s)  Combination Info  click to show the detail info of this combination
                    Name Galangin   NP Info  + TNF-related apoptosis inducing ligand    Drug Info 
                    Structure +
                    Drug Combination 29 Down-regulating the Expression of This Molecule [29]
                    Detail(s)  Combination Info  click to show the detail info of this combination
                    Name Wogonin   NP Info  + ABT-263   Drug Info 
                    Structure +
                    Drug Combination 30 Down-regulating the Expression of This Molecule [30]
                    Detail(s)  Combination Info  click to show the detail info of this combination
                    Name Arsenic trioxide   NP Info  + Lonidamine   Drug Info 
                    Structure +
                    Drug Combination 31 Down-regulating the Expression of This Molecule [31]
                    Detail(s)  Combination Info  click to show the detail info of this combination
                    Name Arsenic trioxide   NP Info  + Rapamycin   Drug Info 
                    Structure +
                    Drug Combination 32 Down-regulating the Expression of This Molecule [32]
                    Detail(s)  Combination Info  click to show the detail info of this combination
                    Name Vincristine   NP Info  + Vorinostat   Drug Info 
                    Structure +
                    Drug Combination 33 Down-regulating the Expression of This Molecule [33]
                    Detail(s)  Combination Info  click to show the detail info of this combination
                    Name Luteolin   NP Info  + TNF-related apoptosis inducing ligand    Drug Info 
                    Structure +
                    Drug Combination 34 Down-regulating the Expression of This Molecule [34]
                    Detail(s)  Combination Info  click to show the detail info of this combination
                    Name Curcumin   NP Info  + Dactolisib   Drug Info 
                    Structure +
                    Drug Combination 35 Down-regulating the Expression of This Molecule [20]
                    Detail(s)  Combination Info  click to show the detail info of this combination
                    Name Silibinin   NP Info  + Trichostatin A   Drug Info 
                    Structure +
                    Drug Combination 36 Down-regulating the Expression of This Molecule [35]
                    Detail(s)  Combination Info  click to show the detail info of this combination
                    Name Amentoflavone   NP Info  + Sorafenib   Drug Info 
                    Structure +
                 Up-regulation     Click to Show/Hide
                    Drug Combination 1 Up-regulating the Expression of This Molecule [37]
                    Detail(s)  Combination Info  click to show the detail info of this combination
                    Name Fisetin   NP Info  + Cabazitaxel   Drug Info 
                    Structure +
          Phosphorylation Regulation     Click to Show/Hide the Drug Combination Regulating This Molecule
                 Down-regulation     Click to Show/Hide
                    Drug Combination 1 Down-regulating the Phosphorylation of This Molecule [36]
                    Detail(s)  Combination Info  click to show the detail info of this combination
                    Name Neferine   NP Info  + Imatinib   Drug Info 
                    Structure +
                 Up-regulation     Click to Show/Hide
                    Drug Combination 1 Up-regulating the Phosphorylation of This Molecule [38]
                    Detail(s)  Combination Info  click to show the detail info of this combination
                    Name Arsenic trioxide   NP Info  + Buthionine sulfoximine   Drug Info 
                    Structure +
Natural Product(s) of This Target
1 Amentoflavone  NP Info  Investigative Gingko biloba
2 Morin  NP Info  Investigative Morus serrata
3 Rosmarinic acid  NP Info  Investigative Salvia rosmarinus
References
Reference 1 Dicoumarol potentiates cisplatin-induced apoptosis mediated by c-Jun N-terminal kinase in p53 wild-type urogenital cancer cell lines. Oncogene. 2006 Apr 20;25(17):2500-8.
Reference 2 Herbal compound triptolide synergistically enhanced antitumor activity of vasostatin120-180. Anticancer Drugs. 2013 Oct;24(9):945-57.
Reference 3 Synergistic antitumor activity of gemcitabine combined with triptolide in pancreatic cancer cells. Oncol Lett. 2016 May;11(5):3527-3533.
Reference 4 Fisetin, a phytochemical, potentiates sorafenib-induced apoptosis and abrogates tumor growth in athymic nude mice implanted with BRAF-mutated melanoma cells. Oncotarget. 2015 Sep 29;6(29):28296-311.
Reference 5 Shikonin sensitizes A549 cells to TRAIL-induced apoptosis through the JNK, STAT3 and AKT pathways. BMC Cell Biol. 2018 Dec 29;19(1):29.
Reference 6 Combining triptolide with ABT-199 is effective against acute myeloid leukemia through reciprocal regulation of Bcl-2 family proteins and activation of the intrinsic apoptotic pathway. Cell Death Dis. 2020 Jul 22;11(7):555.
Reference 7 5-Fluorouracil combined with apigenin enhances anticancer activity through induction of apoptosis in human breast cancer MDA-MB-453 cells. Oncol Rep. 2009 Dec;22(6):1533-7.
Reference 8 Mechanism of synergy of BH3 mimetics and paclitaxel in chronic myeloid leukemia cells: Mcl-1 inhibition. Eur J Pharm Sci. 2015 Apr 5;70:64-71.
Reference 9 Apigenin sensitizes colon cancer cells to antitumor activity of ABT-263. Mol Cancer Ther. 2013 Dec;12(12):2640-50.
Reference 10 Magnolol Enhances the Therapeutic Effects of TRAIL through DR5 Upregulation and Downregulation of c-FLIP and Mcl-1 Proteins in Cancer Cells. Molecules. 2020 Oct 8;25(19):4591.
Reference 11 Degradation of MCL-1 by bufalin reverses acquired resistance to osimertinib in EGFR-mutant lung cancer. Toxicol Appl Pharmacol. 2019 Sep 15;379:114662.
Reference 12 (-)Gossypol and its combination with imatinib induce apoptosis in human chronic myeloid leukemic cells. Leuk Lymphoma. 2007 Nov;48(11):2204-12.
Reference 13 Triptolide sensitizes cisplatin-resistant human epithelial ovarian cancer by inhibiting the phosphorylation of AKT. J Cancer. 2019 Jun 2;10(13):3012-3020.
Reference 14 Synergistic growth inhibition by sorafenib and vitamin K2 in human hepatocellular carcinoma cells. Clinics (Sao Paulo). 2012 Sep;67(9):1093-9.
Reference 15 ABT-737 synergizes with arsenic trioxide to induce apoptosis of gastric carcinoma cells in vitro and in vivo. J Int Med Res. 2012;40(4):1251-64.
Reference 16 Overcoming acquired resistance of EGFR-mutant NSCLC cells to the third generation EGFR inhibitor, osimertinib, with the natural product honokiol. Mol Oncol. 2020 Apr;14(4):882-895.
Reference 17 Belinostat and vincristine demonstrate mutually synergistic cytotoxicity associated with mitotic arrest and inhibition of polyploidy in a preclinical model of aggressive diffuse large B cell lymphoma. Cancer Biol Ther. 2016 Dec;17(12):1240-1252.
Reference 18 Bufalin and 5-fluorouracil synergistically induce apoptosis in colorectal cancer cells. Oncol Lett. 2018 May;15(5):8019-8026.
Reference 19 Down-regulation of Cbl-b by bufalin results in up-regulation of DR4/DR5 and sensitization of TRAIL-induced apoptosis in breast cancer cells. J Cancer Res Clin Oncol. 2012 Aug;138(8):1279-89.
Reference 20 Epigenetic modifications and p21-cyclin B1 nexus in anticancer effect of histone deacetylase inhibitors in combination with silibinin on non-small cell lung cancer cells. Epigenetics. 2012 Oct;7(10):1161-72.
Reference 21 Flavopiridol enhances ABT-199 sensitivity in unfavourable-risk multiple myeloma cells in vitro and in vivo. Br J Cancer. 2018 Feb 6;118(3):388-397.
Reference 22 NOX4-mediated ROS production induces apoptotic cell death via down-regulation of c-FLIP and Mcl-1 expression in combined treatment with thioridazine and curcumin. Redox Biol. 2017 Oct;13:608-622.
Reference 23 Combined treatment with sorafenib and silibinin synergistically targets both HCC cells and cancer stem cells by enhanced inhibition of the phosphorylation of STAT3/ERK/AKT. Eur J Pharmacol. 2018 Aug 5;832:39-49.
Reference 24 Vernodalol enhances TRAIL-induced apoptosis in diffuse large B-cell lymphoma cells. Mol Carcinog. 2017 Oct;56(10):2190-2199.
Reference 25 Gambogic acid induces apoptosis in imatinib-resistant chronic myeloid leukemia cells via inducing proteasome inhibition and caspase-dependent Bcr-Abl downregulation. Clin Cancer Res. 2014 Jan 1;20(1):151-63.
Reference 26 Betulinic acid promotes TRAIL function on liver cancer progression inhibition through p53/Caspase-3 signaling activation. Biomed Pharmacother. 2017 Apr;88:349-358.
Reference 27 The antileukemia roles of PP242 alone or in combination with daunorubicin in acute leukemia. Anticancer Drugs. 2015 Apr;26(4):410-21.
Reference 28 Galangin sensitizes TRAIL-induced apoptosis through down-regulation of anti-apoptotic proteins in renal carcinoma Caki cells. Sci Rep. 2016 Jan 4;6:18642.
Reference 29 Targeting CDK9 by wogonin and related natural flavones potentiates the anti-cancer efficacy of the Bcl-2 family inhibitor ABT-263. Int J Cancer. 2015 Feb 1;136(3):688-98.
Reference 30 Increased apoptotic efficacy of lonidamine plus arsenic trioxide combination in human leukemia cells. Reactive oxygen species generation and defensive protein kinase (MEK/ERK, Akt/mTOR) modulation. Biochem Pharmacol. 2011 Dec 1;82(11):1619-29.
Reference 31 Arsenic trioxide overcomes rapamycin-induced feedback activation of AKT and ERK signaling to enhance the anti-tumor effects in breast cancer. PLoS One. 2013 Dec 31;8(12):e85995.
Reference 32 The synergic effect of vincristine and vorinostat in leukemia in vitro and in vivo. J Hematol Oncol. 2015 Jul 10;8:82.
Reference 33 The combination of TRAIL and luteolin enhances apoptosis in human cervical cancer HeLa cells. Biochem Biophys Res Commun. 2005 Aug 5;333(3):833-8.
Reference 34 Curcumin significantly enhances dual PI3K/Akt and mTOR inhibitor NVP-BEZ235-induced apoptosis in human renal carcinoma Caki cells through down-regulation of p53-dependent Bcl-2 expression and inhibition of Mcl-1 protein stability. PLoS One. 2014 Apr 17;9(4):e95588.
Reference 35 Amentoflavone enhances sorafenib-induced apoptosis through extrinsic and intrinsic pathways in sorafenib-resistant hepatocellular carcinoma SK-Hep1 cells in vitro. Oncol Lett. 2017 Sep;14(3):3229-3234.
Reference 36 Neferine increases STI571 chemosensitivity via inhibition of P-gp expression in STI571-resistant K562 cells. Leuk Lymphoma. 2011 Apr;52(4):694-700.
Reference 37 Fisetin Enhances Chemotherapeutic Effect of Cabazitaxel against Human Prostate Cancer Cells. Mol Cancer Ther. 2016 Dec;15(12):2863-2874.
Reference 38 Arsenic trioxide-induced apoptosis and its enhancement by buthionine sulfoximine in hepatocellular carcinoma cell lines. Biochem Biophys Res Commun. 2002 Mar 8;291(4):861-7.
Reference 39 In silico identification and biochemical evaluation of novel inhibitors of NRH:quinone oxidoreductase 2 (NQO2). Bioorg Med Chem Lett. 2010 Dec 15;20(24):7331-6.
Cite NPCDR
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Correspondence

X. N. Sun, Y. T. Zhang, Y. Zhou, X. C. Lian, L. L. Yan, T. Pan, T. Jin, H. Xie, Z. M. Liang, W. Q. Qiu, J. X. Wang, Z. R. Li, F. Zhu*, X. B. Sui*. NPCDR: natural product-based drug combination and its disease-specific molecular regulation. Nucleic Acids Research. 50(D1): 1324-1333 (2020). PMID: 34664659

Prof. Feng ZHU  (zhufeng@zju.edu.cn)

College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China


Prof. Xinbing SUI  (hzzju@hznu.edu.cn)

School of Pharmacy and Department of Medical Oncology, the Affiliated Hospital of Hangzhou Normal University, Hangzhou Normal University, Hangzhou, China