{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,3]],"date-time":"2026-03-03T03:02:18Z","timestamp":1772506938155,"version":"3.50.1"},"reference-count":41,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2021,8,20]],"date-time":"2021-08-20T00:00:00Z","timestamp":1629417600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Competitiveness and Excellence Programme","award":["NVKP_16-1-2016-0036"],"award-info":[{"award-number":["NVKP_16-1-2016-0036"]}]},{"name":"New National Excellence Program of the Ministry for Innovation and Technology","award":["\u00daNKP-19-3-I-SE-49"],"award-info":[{"award-number":["\u00daNKP-19-3-I-SE-49"]}]},{"DOI":"10.13039\/501100015498","name":"Ministry for Innovation and Technology","doi-asserted-by":"publisher","award":["EFOP-3.6.3-VEKOP-16-2017-00009 program"],"award-info":[{"award-number":["EFOP-3.6.3-VEKOP-16-2017-00009 program"]}],"id":[{"id":"10.13039\/501100015498","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>Combination antitumor treatments are essential parts of modern tumor therapy as\u2014compared to monotherapies\u2014(i) they are more effective; (ii) the dose of the compounds can be reduced; and (iii) therefore the side effects are improved. Our research group previously demonstrated the antitumor character of bortezomib (BOZ) in A2058 melanoma cells. Unfortunately, dose-related side effects are common during BOZ therapy, which could be prevented by reducing the dose of BOZ. This study aimed to characterize synergistic combinations of BOZ with a TRAIL (TNF-related apoptosis-inducing ligand) -inducing compound (TIC10), where the doses can be cut down but the efficacy is preserved. Endpoint cell viability assays were performed on A2058 cells, and synergism of BOZ and TIC10 was observed after 72 h. Synergism was further validated in a real-time impedimetric assay, and our results showed that BOZ-treated melanoma cells survived the treatment, an effect not registered in the co-treatments. Treatment with the combinations resulted in increased apoptosis, which was not accompanied by enhanced LDH release. Nevertheless, the expression of death receptor 5 (DR5) was increased on the cell surface without transcriptional regulation. In summary, our findings support the theory that the application of BOZ and TIC10 in combination could provide higher efficacy in vitro.<\/jats:p>","DOI":"10.3390\/ph14080820","type":"journal-article","created":{"date-parts":[[2021,8,22]],"date-time":"2021-08-22T22:59:27Z","timestamp":1629673167000},"page":"820","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["The Synergistic Activity of Bortezomib and TIC10 against A2058 Melanoma Cells"],"prefix":"10.3390","volume":"14","author":[{"given":"Ang\u00e9la","family":"Tak\u00e1cs","sequence":"first","affiliation":[{"name":"Department of Genetics, Cell and Immunobiology, Semmelweis University, H-1089 Budapest, Hungary"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zs\u00f3fia","family":"Sz\u00e1sz","sequence":"additional","affiliation":[{"name":"Department of Genetics, Cell and Immunobiology, Semmelweis University, H-1089 Budapest, Hungary"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"M\u00e1rton","family":"Kalabay","sequence":"additional","affiliation":[{"name":"Department of Genetics, Cell and Immunobiology, Semmelweis University, H-1089 Budapest, Hungary"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"P\u00e9ter","family":"B\u00e1r\u00e1ny","sequence":"additional","affiliation":[{"name":"Department of Organic Chemistry, Institute of Chemistry, E\u00f6tv\u00f6s Lor\u00e1nd University, H-1117 Budapest, Hungary"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2107-7309","authenticated-orcid":false,"given":"Antal","family":"Cs\u00e1mpai","sequence":"additional","affiliation":[{"name":"Department of Organic Chemistry, Institute of Chemistry, E\u00f6tv\u00f6s Lor\u00e1nd University, H-1117 Budapest, Hungary"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hargita","family":"Hegyesi","sequence":"additional","affiliation":[{"name":"Department of Genetics, Cell and Immunobiology, Semmelweis University, H-1089 Budapest, Hungary"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Orsolya","family":"L\u00e1ng","sequence":"additional","affiliation":[{"name":"Department of Genetics, Cell and Immunobiology, Semmelweis University, H-1089 Budapest, Hungary"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4796-4646","authenticated-orcid":false,"given":"Eszter","family":"Lajk\u00f3","sequence":"additional","affiliation":[{"name":"Department of Genetics, Cell and Immunobiology, Semmelweis University, H-1089 Budapest, Hungary"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9002-0296","authenticated-orcid":false,"given":"L\u00e1szl\u00f3","family":"K\u0151hidai","sequence":"additional","affiliation":[{"name":"Department of Genetics, Cell and Immunobiology, Semmelweis University, H-1089 Budapest, Hungary"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2021,8,20]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"562","DOI":"10.3349\/ymj.2020.61.7.562","article-title":"KIT and Melanoma: Biological Insights and Clinical Implications","volume":"61","author":"Pham","year":"2020","journal-title":"Yonsei Med. J."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"adv00139","DOI":"10.2340\/00015555-3494","article-title":"Melanoma Risk and Melanocyte Biology","volume":"100","author":"Bertrand","year":"2020","journal-title":"Acta Derm. Venereol."},{"key":"ref_3","first-page":"1071","article-title":"Cutaneous melanoma: From pathogenesis to therapy (Review)","volume":"52","author":"Leonardi","year":"2018","journal-title":"Int. J. Oncol."},{"key":"ref_4","first-page":"1005","article-title":"Melanoma: Epidemiology, Risk Factors, Pathogenesis, Diagnosis and Classification","volume":"28","author":"Rastrelli","year":"2014","journal-title":"In Vivo"},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Simiczyjew, A., Dratkiewicz, E., Mazurkiewicz, J., Zi\u0119tek, M., Matkowski, R., and Nowak, D. (2020). The Influence of Tumor Microenvironment on Immune Escape of Melanoma. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21218359"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1435","DOI":"10.1016\/j.annonc.2020.07.004","article-title":"ESMO consensus conference recommendations on the management of metastatic melanoma: Under the auspices of the ESMO Guidelines Committee","volume":"31","author":"Keilholz","year":"2020","journal-title":"Ann. Oncol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"313","DOI":"10.1016\/j.bbcan.2019.02.002","article-title":"Many ways to resistance: How melanoma cells evade targeted therapies","volume":"1871","author":"Kozar","year":"2019","journal-title":"Biochim. Biophys. Acta Rev. Cancer"},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Steininger, J., Gellrich, F.F., Schulz, A., Westphal, D., Beissert, S., and Meier, F. (2021). Systemic Therapy of Metastatic Melanoma: On the Road to Cure. Cancers, 13.","DOI":"10.3390\/cancers13061430"},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Gurunathan, S., Kang, M.H., Qasim, M., and Kim, J.H. (2018). Nanoparticle-Mediated Combination Therapy: Two-in-One Approach for Cancer. Int. J. Mol. Sci., 19.","DOI":"10.3390\/ijms19103264"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"14287","DOI":"10.1038\/s41598-020-71138-z","article-title":"Alpha-lipoic acid alters the antitumor effect of bortezomib in melanoma cells in vitro","volume":"10","author":"Istenes","year":"2020","journal-title":"Sci. Rep."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1097\/CJI.0000000000000009","article-title":"A phase I trial of bortezomib and interferon-\u03b1-2b in metastatic melanoma","volume":"37","author":"Markowitz","year":"2014","journal-title":"J. Immunother."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"174","DOI":"10.3389\/fnmol.2017.00174","article-title":"Pathophysiology of Chemotherapy-Induced Peripheral Neuropathy","volume":"10","author":"Starobova","year":"2017","journal-title":"Front. Mol. Neurosci."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"619","DOI":"10.1007\/s10637-017-0531-3","article-title":"Phase I trial of bortezomib daily dose: Safety, pharmacokinetic profile, biological effects and early clinical evaluation in patients with advanced solid tumors","volume":"36","author":"Bahleda","year":"2018","journal-title":"Investig. New Drugs"},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"B\u00e1r\u00e1ny, P., Ol\u00e1h, R.S., Kov\u00e1cs, I., Czuczi, T., Szab\u00f3, C.L., Tak\u00e1cs, A., Lajk\u00f3, E., L\u00e1ng, O., K\u0151hidai, L., and Schlosser, G. (2018). Ferrocene-Containing Impiridone (ONC201) Hybrids: Synthesis, DFT Modelling, In Vitro Evaluation, and Structure\u2014Activity Relationships. Molecules, 23.","DOI":"10.3390\/molecules23092248"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"21626","DOI":"10.18632\/oncotarget.15451","article-title":"ONC201 activates ER stress to inhibit the growth of triple-negative breast cancer cells","volume":"8","author":"Yuan","year":"2017","journal-title":"Oncotarget"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"725","DOI":"10.1016\/j.neo.2020.09.005","article-title":"ONC201 and imipridones: Anti-cancer compounds with clinical efficacy","volume":"22","author":"Prabhu","year":"2020","journal-title":"Neoplasia"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"S1439","DOI":"10.21037\/tcr.2017.10.51","article-title":"TIC10\/ONC201-a potential therapeutic in glioblastoma","volume":"6","author":"Siegelin","year":"2017","journal-title":"Transl. Cancer Res."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"8628","DOI":"10.1038\/sj.onc.1207232","article-title":"TRAIL and apoptosis induction by TNF-family death receptors","volume":"22","author":"Wang","year":"2003","journal-title":"Oncogene"},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Oh, Y.T., and Sun, S.Y. (2021). Regulation of Cancer Metastasis by TRAIL\/Death Receptor Signaling. Biomolecules, 11.","DOI":"10.3390\/biom11040499"},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"\u0410rtykov, \u0410., Belov, D.A., Shipunova, V.O., Trushina, D.B., Deyev, S.M., Dolgikh, D.A., Kirpichnikov, M.P., and Gasparian, M.E. (2020). Chemotherapeutic Agents Sensitize Resistant Cancer Cells to the DR5-Specific Variant DR5-B more Efficiently than to TRAIL by Modulating the Surface Expression of Death and Decoy Receptors. Cancers, 12.","DOI":"10.3390\/cancers12051129"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"4981","DOI":"10.1158\/0008-5472.CAN-06-4274","article-title":"The proteasome inhibitor PS-341 (bortezomib) up-regulates DR5 expression leading to induction of apoptosis and enhancement of TRAIL-induced apoptosis despite up-regulation of c-FLIP and survivin expression in human NSCLC cells","volume":"67","author":"Liu","year":"2007","journal-title":"Cancer Res."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"75","DOI":"10.18632\/oncoscience.133","article-title":"TIC10\/ONC201: A bend in the road to clinical development","volume":"2","author":"Greer","year":"2015","journal-title":"Oncoscience"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1146","DOI":"10.1038\/s41416-020-0759-0","article-title":"Dual metabolic reprogramming by ONC201\/TIC10 and 2-Deoxyglucose induces energy depletion and synergistic anti-cancer activity in glioblastoma","volume":"122","author":"Pruss","year":"2020","journal-title":"Br. J. Cancer"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"e573","DOI":"10.3747\/co.21.1798","article-title":"Bortezomib in multiple myeloma: Systematic review and clinical considerations","volume":"21","author":"Kouroukis","year":"2014","journal-title":"Curr. Oncol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"417","DOI":"10.1038\/nrclinonc.2016.206","article-title":"Proteasome inhibitors in cancer therapy","volume":"14","author":"Manasanch","year":"2017","journal-title":"Nat. Rev. Clin. Oncol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"2059","DOI":"10.1080\/10428190802353591","article-title":"Preclinical versus clinical drug combination studies","volume":"49","author":"Chou","year":"2008","journal-title":"Leuk. Lymphoma"},{"key":"ref_27","unstructured":"Chen, X., and Thibeault, S. (2013, January 3\u20137). Effect of DMSO concentration, cell density and needle gauge on the viability of cryopreserved cells in three dimensional hyaluronan hydrogel. Proceedings of the Annual International Conference of the IEEE Engineering in Medicine and Biology Society (EMBC), Osaka, Japan."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Yan, G., Du, Q., Wei, X., Miozzi, J., Kang, C., Wang, J., Han, X., Pan, J., Xie, H., and Chen, J. (2018). Application of Real-Time Cell Electronic Analysis System in Modern Pharmaceutical Evaluation and Analysis. Molecules, 23.","DOI":"10.3390\/molecules23123280"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1186\/2050-7771-1-13","article-title":"The resistance mechanisms of proteasome inhibitor bortezomib","volume":"1","author":"Wang","year":"2013","journal-title":"Biomark. Res."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"240","DOI":"10.1016\/j.leukres.2005.06.014","article-title":"No evidence of mutations of the PSMB5 (beta-5 subunit of proteasome) in a case of myeloma with clinical resistance to Bortezomib","volume":"30","author":"Politou","year":"2006","journal-title":"Leuk Res."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"207","DOI":"10.1016\/j.bcp.2011.10.009","article-title":"Proteasome-based mechanisms of intrinsic and acquired bortezomib resistance in non-small cell lung cancer","volume":"83","author":"Jansen","year":"2012","journal-title":"Biochem. Pharm."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"468","DOI":"10.1080\/15384101.2017.1403689","article-title":"Single agent and synergistic combinatorial efficacy of first-in-class small molecule imipridone ONC201 in hematological malignancies","volume":"17","author":"Prabhu","year":"2018","journal-title":"Cell Cycle"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"ra17","DOI":"10.1126\/scisignal.aac4380","article-title":"ATF4 induction through an atypical integrated stress response to ONC201 triggers p53-independent apoptosis in hematological malignancies","volume":"9","author":"Ishizawa","year":"2016","journal-title":"Sci. Signal"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"171ra117","DOI":"10.1126\/scitranslmed.3004828","article-title":"Dual inactivation of Akt and ERK by TIC10 signals Foxo3a nuclear translocation, TRAIL gene induction, and potent antitumor effects","volume":"5","author":"Allen","year":"2013","journal-title":"Sci. Transl. Med."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1186\/s12943-015-0346-9","article-title":"Identification of TRAIL-inducing compounds highlights small molecule ONC201\/TIC10 as a unique anti-cancer agent that activates the TRAIL pathway","volume":"14","author":"Allen","year":"2015","journal-title":"Mol. Cancer"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"36456","DOI":"10.18632\/oncotarget.5505","article-title":"TIC10\/ONC201 synergizes with Bcl-2\/Bcl-xL inhibition in glioblastoma by suppression of Mcl-1 and its binding partners in vitro and in vivo","volume":"6","author":"Shu","year":"2015","journal-title":"Oncotarget"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1126\/science.276.5309.111","article-title":"The receptor for the cytotoxic ligand TRAIL","volume":"276","author":"Pan","year":"1997","journal-title":"Science"},{"key":"ref_38","first-page":"3734","article-title":"Expression of TRAIL and TRAIL receptors in colon carcinoma: TRAIL-R1 is an independent prognostic parameter","volume":"8","author":"Hinz","year":"2002","journal-title":"Clin. Cancer Res. Off. J. Am. Assoc. Cancer Res."},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Bychkov, M.L., Gasparian, M.E., Dolgikh, D.A., and Kirpichnikov, M.P. (2014). Combination of TRAIL with bortezomib shifted apoptotic signaling from DR4 to DR5 death receptor by selective internalization and degradation of DR4. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0109756"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"440","DOI":"10.1158\/0008-5472.CAN-09-1947","article-title":"Drug Combination Studies and Their Synergy Quantification Using the Chou-Talalay Method","volume":"70","author":"Chou","year":"2010","journal-title":"Cancer Res."},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Kumar, P., Nagarajan, A., and Uchil, P.D. (2018). Analysis of Cell Viability by the Lactate Dehydrogenase Assay. Cold Spring Harb. Protoc., 2018.","DOI":"10.1101\/pdb.prot095497"}],"container-title":["Pharmaceuticals"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1424-8247\/14\/8\/820\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T06:48:23Z","timestamp":1760165303000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1424-8247\/14\/8\/820"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,8,20]]},"references-count":41,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2021,8]]}},"alternative-id":["ph14080820"],"URL":"https:\/\/doi.org\/10.3390\/ph14080820","relation":{},"ISSN":["1424-8247"],"issn-type":[{"value":"1424-8247","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,8,20]]}}}