Novel Erlotinib–Chalcone Hybrids Diminish Resistance in Head and Neck Cancer by Inducing Multiple Cell Death Mechanisms
Abstract
:1. Introduction
2. Results
2.1. Chemistry
2.2. In Vitro Cell Viability Inhibition Screening of Novel Erlotinib–Chalcone Hybrid Molecules on HNSCC Cell Lines
2.3. Time- and Dose-Dependent Effects of Selected Hybrid Molecules on the Viability of HNSCC Cells
2.4. Colony Formation Assay
2.5. Apoptosis and Necrosis Quantitation Assay
2.6. Mitochondrial Membrane Potential Detection
2.7. Real-Time Apoptosis Detection
3. Discussion
4. Materials and Methods
4.1. Cell Culturing
4.2. CellTiter-Glo Cell Viability Assay
4.3. Colony Formation Assay
4.4. Apoptosis and Necrosis Quantitation Assay
4.5. Mitochondrial Membrane Potential Detection
4.6. Real-Time Apoptosis Detection
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
- Sung, H.; Ferlay, J.; Siegel, R.L.; Laversanne, M.; Soerjomataram, I.; Jemal, A.; Bray, F. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J. Clin. 2021, 71, 209–249. [Google Scholar] [CrossRef]
- Johnson, D.E.; Burtness, B.; Leemans, C.R.; Lui, V.W.Y.; Bauman, J.E.; Grandis, J.R. Head and neck squamous cell carcinoma. Nat. Rev. Dis. Primers. 2020, 6, 92. [Google Scholar] [CrossRef]
- Goel, B.; Tiwari, A.K.; Pandey, R.K.; Singh, A.P.; Kumar, S.; Sinha, A.; Jain, S.K.; Khattri, A. Therapeutic approaches for the treatment of head and neck squamous cell carcinoma-An update on clinical trials. Transl. Oncol. 2022, 21, 101426. [Google Scholar] [CrossRef]
- Lurje, G.; Lenz, H.J. EGFR signaling and drug discovery. Oncology 2009, 77, 400–410. [Google Scholar] [CrossRef]
- Papini, F.; Sundaresan, J.; Leonetti, A.; Tiseo, M.; Rolfo, C.; Peters, G.J.; Giovannetti, E. Hype or hope—Can combination therapies with third-generation EGFR-TKIs help overcome acquired resistance and improve outcomes in EGFR-mutant advanced/metastatic NSCLC? Crit. Rev. Oncol./Hematol. 2021, 166, 103454. [Google Scholar] [CrossRef]
- Fortin, S.; Bérubé, G. Advances in the development of hybrid anticancer drugs. Expert Opin. Drug Discov. 2013, 8, 1029–1047. [Google Scholar] [CrossRef]
- Kucuksayan, E.; Ozben, T. Hybrid Compounds as Multitarget Directed Anticancer Agents. Curr. Top. Med. Chem. 2017, 17, 907–918. [Google Scholar] [CrossRef]
- Zheng, W.; Zhao, Y.; Luo, Q.; Zhang, Y.; Wu, K.; Wang, F. Multi-Targeted Anticancer Agents. Curr Top. Med Chem 2017, 17, 3084–3098. [Google Scholar] [CrossRef]
- Sharma, V.; Kumar, V.; Kumar, P. Heterocyclic chalcone analogues as potential anticancer agents. Anticancer Agents Med. Chem. 2013, 13, 422–432. [Google Scholar]
- Karthikeyan, C.; Moorthy, N.S.; Ramasamy, S.; Vanam, U.; Manivannan, E.; Karunagaran, D.; Trivedi, P. Advances in chalcones with anticancer activities. Recent Pat. Anticancer. Drug Discov. 2015, 10, 97–115. [Google Scholar] [CrossRef]
- Mahapatra, D.K.; Bharti, S.K.; Asati, V. Anti-cancer chalcones: Structural and molecular target perspectives. Eur. J. Med. Chem. 2015, 98, 69–114. [Google Scholar] [CrossRef]
- Gao, F.; Huang, G.; Xiao, J. Chalcone hybrids as potential anticancer agents: Current development, mechanism of action, and structure-activity relationship. Med. Res. Rev. 2020, 40, 2049–2084. [Google Scholar] [CrossRef]
- Shukla, S.; Sood, A.K.; Goyal, K.; Singh, A.; Sharma, V.; Guliya, N.; Gulati, S.; Kumar, S. Chalcone Scaffolds as Anticancer Drugs: A Review on Molecular Insight in Action of Mechanisms and Anticancer Properties. Anticancer Agents Med. Chem. 2021, 21, 1650–1670. [Google Scholar] [CrossRef]
- Srinivasan, B.; Johnson, T.E.; Lad, R.; Xing, C. Structure-activity relationship studies of chalcone leading to 3-hydroxy-4,3’,4’,5’-tetramethoxychalcone and its analogues as potent nuclear factor kappaB inhibitors and their anticancer activities. J. Med. Chem. 2009, 52, 7228–7235. [Google Scholar] [CrossRef]
- Jernei, T.; Duró, C.; Dembo, A.; Lajkó, E.; Takács, A.; Kőhidai, L.; Schlosser, G.; Csámpai, A. Synthesis, Structure and In Vitro Cytotoxic Activity of Novel Cinchona-Chalcone Hybrids with 1,4-Disubstituted- and 1,5-Disubstituted 1,2,3-Triazole Linkers. Molecules 2019, 24, 4077. [Google Scholar] [CrossRef]
- Riaz, S.; Iqbal, M.; Ullah, R.; Zahra, R.; Chotana, G.A.; Faisal, A.; Saleem, R.S.Z. Synthesis and evaluation of novel α-substituted chalcones with potent anti-cancer activities and ability to overcome multidrug resistance. Bioorg. Chem. 2019, 87, 123–135. [Google Scholar] [CrossRef]
- Xiao, J.; Gao, M.; Diao, Q.; Gao, F. Chalcone Derivatives and their Activities against Drug-resistant Cancers: An Overview. Curr. Top. Med. Chem. 2021, 21, 348–362. [Google Scholar] [CrossRef]
- Latif, A.D.; Jernei, T.; Podolski-Renić, A.; Kuo, C.Y.; Vágvölgyi, M.; Girst, G.; Zupkó, I.; Develi, S.; Ulukaya, E.; Wang, H.C.; et al. Protoflavone-Chalcone Hybrids Exhibit Enhanced Antitumor Action through Modulating Redox Balance, Depolarizing the Mitochondrial Membrane, and Inhibiting ATR-Dependent Signaling. Antioxidants 2020, 9, 519. [Google Scholar] [CrossRef]
- Yadav, P.; Lal, K.; Kumar, A.; Guru, S.K.; Jaglan, S.; Bhushan, S. Green synthesis and anticancer potential of chalcone linked-1,2,3-triazoles. Eur. J. Med. Chem. 2017, 126, 944–953. [Google Scholar] [CrossRef]
- Podolski-Renić, A.; Bősze, S.; Dinić, J.; Kocsis, L.; Hudecz, F.; Csámpai, A.; Pešić, M. Ferrocene-cinchona hybrids with triazolyl-chalcone linkers act as pro-oxidants and sensitize human cancer cell lines to paclitaxel. Metallomics 2017, 9, 1132–1141. [Google Scholar] [CrossRef]
- Kocsis, L.; Szabó, I.; Bősze, S.; Jernei, T.; Hudecz, F.; Csámpai, A. Synthesis, structure and in vitro cytostatic activity of ferrocene-Cinchona hybrids. Bioorg. Med. Chem. Lett. 2016, 26, 946–949. [Google Scholar] [CrossRef] [Green Version]
- Bonandi, E.; Christodoulou, M.S.; Fumagalli, G.; Perdicchia, D.; Rastelli, G.; Passarella, D. The 1,2,3-triazole ring as a bioisostere in medicinal chemistry. Drug Discov. Today 2017, 22, 1572–1581. [Google Scholar] [CrossRef]
- Bozorov, K.; Zhao, J.; Aisa, H.A. 1,2,3-Triazole-containing hybrids as leads in medicinal chemistry: A recent overview. Bioorg. Med. Chem. 2019, 27, 3511–3531. [Google Scholar] [CrossRef]
- Pereira, D.; Pinto, M.; Correia-da-Silva, M.; Cidade, H. Recent Advances in Bioactive Flavonoid Hybrids Linked by 1,2,3-Triazole Ring Obtained by Click Chemistry. Molecules 2021, 27, 230. [Google Scholar] [CrossRef]
- Dheer, D.; Singh, V.; Shankar, R. Medicinal attributes of 1,2,3-triazoles: Current developments. Bioorg. Chem. 2017, 71, 30–54. [Google Scholar] [CrossRef]
- Chu, X.M.; Wang, C.; Wang, W.L.; Liang, L.L.; Liu, W.; Gong, K.K.; Sun, K.L. Triazole derivatives and their antiplasmodial and antimalarial activities. Eur. J. Med. Chem. 2019, 166, 206–223. [Google Scholar] [CrossRef]
- Feng, L.S.; Xu, Z.; Chang, L.; Li, C.; Yan, X.F.; Gao, C.; Ding, C.; Zhao, F.; Shi, F.; Wu, X. Hybrid molecules with potential in vitro antiplasmodial and in vivo antimalarial activity against drug-resistant Plasmodium falciparum. Med. Res. Rev. 2020, 40, 931–971. [Google Scholar] [CrossRef]
- Pingaew, R.; Saekee, A.; Mandi, P.; Nantasenamat, C.; Prachayasittikul, S.; Ruchirawat, S.; Prachayasittikul, V. Synthesis, biological evaluation and molecular docking of novel chalcone-coumarin hybrids as anticancer and antimalarial agents. Eur. J. Med. Chem. 2014, 85, 65–76. [Google Scholar] [CrossRef]
- Zhang, B. Comprehensive review on the anti-bacterial activity of 1,2,3-triazole hybrids. Eur. J. Med. Chem. 2019, 168, 357–372. [Google Scholar] [CrossRef]
- Xu, Z. 1,2,3-Triazole-containing hybrids with potential antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA). Eur. J. Med. Chem. 2020, 206, 112686. [Google Scholar] [CrossRef]
- Rani, A.; Singh, G.; Singh, A.; Maqbool, U.; Kaur, G.; Singh, J. CuAAC-ensembled 1,2,3-triazole-linked isosteres as pharmacophores in drug discovery: Review. RSC Adv. 2020, 10, 5610–5635. [Google Scholar] [CrossRef]
- Slavova, K.I.; Todorov, L.T.; Belskaya, N.P.; Palafox, M.A.; Kostova, I.P. Developments in the Application of 1,2,3-Triazoles in Cancer Treatment. Recent Pat. Anticancer Drug Discov. 2020, 15, 92–112. [Google Scholar] [CrossRef]
- Lal, K.; Yadav, P. Recent Advancements in 1,4-Disubstituted 1H-1,2,3-Triazoles as Potential Anticancer Agents. Anticancer Agents Med. Chem. 2018, 18, 21–37. [Google Scholar] [CrossRef]
- Liang, T.; Sun, X.; Li, W.; Hou, G.; Gao, F. 1,2,3-Triazole-Containing Compounds as Anti-Lung Cancer Agents: Current Developments, Mechanisms of Action, and Structure-Activity Relationship. Front. Pharmacol. 2021, 12, 661173. [Google Scholar] [CrossRef]
- Siddiq, A.; Dembitsky, V. Acetylenic anticancer agents. Anticancer Agents Med. Chem. 2008, 8, 132–170. [Google Scholar] [CrossRef]
- Kim, J.; Park, E.J. Cytotoxic anticancer candidates from natural resources. Curr. Med. Chem. Anticancer Agents. 2002, 2, 485–537. [Google Scholar] [CrossRef]
- Christensen, L.P. Bioactive C(17) and C(18) Acetylenic Oxylipins from Terrestrial Plants as Potential Lead Compounds for Anticancer Drug Development. Molecules 2020, 25, 2568. [Google Scholar] [CrossRef]
- Wang, S.; Liu, L.; Guo, X.; Li, G.; Wang, X.; Dong, H.; Li, Y.; Zhao, W. Synthesis of novel natural product-like diaryl acetylenes as hypoxia inducible factor-1 inhibitors and antiproliferative agents. RSC Adv. 2019, 9, 13878–13886. [Google Scholar] [CrossRef]
- Yang, C.; Shao, Y.; Li, K.; Xia, W. Bioactive selaginellins from Selaginella tamariscina (Beauv.) Spring. Beilstein J. Org. Chem. 2012, 8, 1884–1889. [Google Scholar] [CrossRef]
- Zhang, G.G.; Jing, Y.; Zhang, H.M.; Ma, E.L.; Guan, J.; Xue, F.N.; Liu, H.X.; Sun, X.Y. Isolation and cytotoxic activity of selaginellin derivatives and biflavonoids from Selaginella tamariscina. Planta Med. 2012, 78, 390–392. [Google Scholar] [CrossRef]
- Wang, C.; Carter-Cooper, B.; Du, Y.; Zhou, J.; Saeed, M.A.; Liu, J.; Guo, M.; Roembke, B.; Mikek, C.; Lewis, E.A.; et al. Alkyne-substituted diminazene as G-quadruplex binders with anticancer activities. Eur. J. Med. Chem. 2016, 118, 266–275. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Ruddarraju, R.R.; Murugulla, A.C.; Kotla, R.; Chandra Babu Tirumalasetty, M.; Wudayagiri, R.; Donthabakthuni, S.; Maroju, R.; Baburao, K.; Parasa, L.S. Design, synthesis, anticancer, antimicrobial activities and molecular docking studies of theophylline containing acetylenes and theophylline containing 1,2,3-triazoles with variant nucleoside derivatives. Eur. J. Med. Chem. 2016, 123, 379–396. [Google Scholar] [CrossRef] [PubMed]
- Rostovtsev, V.V.; Green, L.G.; Fokin, V.V.; Sharpless, K.B. A stepwise huisgen cycloaddition process: Copper(I)-catalyzed regioselective “ligation” of azides and terminal alkynes. Angew. Chem. Int. Ed. 2002, 41, 2596–2599. [Google Scholar] [CrossRef]
- Bonesi, M.; Loizzo, M.R.; Statti, G.A.; Michel, S.; Tillequin, F.; Menichini, F. The synthesis and angiotensin converting enzyme (ACE) inhibitory activity of chalcones and their pyrazole derivatives. Bioorg. Med. Chem. Lett. 2010, 20, 1990–1993. [Google Scholar] [CrossRef]
- Aoki, K.; Satoi, S.; Harada, S.; Uchida, S.; Iwasa, Y.; Ikenouchi, J. Coordinated changes in cell membrane and cytoplasm during maturation of apoptotic bleb. Mol. Biol. Cell. 2020, 31, 833–844. [Google Scholar] [CrossRef]
- Sebbagh, M.; Renvoizé, C.; Hamelin, J.; Riché, N.; Bertoglio, J.; Bréard, J. Caspase-3-mediated cleavage of ROCK I induces MLC phosphorylation and apoptotic membrane blebbing. Nature Cell Biol. 2001, 3, 346–352. [Google Scholar] [CrossRef]
- Sivandzade, F.; Bhalerao, A.; Cucullo, L. Analysis of the Mitochondrial Membrane Potential Using the Cationic JC-1 Dye as a Sensitive Fluorescent Probe. Bio. Protoc. 2019, 9, e3128. [Google Scholar] [CrossRef]
- Desquiret, V.; Loiseau, D.; Jacques, C.; Douay, O.; Malthièry, Y.; Ritz, P.; Roussel, D. Dinitrophenol-induced mitochondrial uncoupling in vivo triggers respiratory adaptation in HepG2 cells. Biochim. Biophys. Acta (BBA)—Bioenerg. 2006, 1757, 21–30. [Google Scholar] [CrossRef]
- Tait, S.W.G.; Green, D.R. Caspase-independent cell death: Leaving the set without the final cut. Oncogene 2008, 27, 6452–6461. [Google Scholar] [CrossRef]
- Bukowski, K.; Kciuk, M.; Kontek, R. Mechanisms of Multidrug Resistance in Cancer Chemotherapy. Int. J. Mol. Sci. 2020, 21, 3233. [Google Scholar] [CrossRef]
- Shen, S.; Vagner, S.; Robert, C. Persistent Cancer Cells: The Deadly Survivors. Cell 2020, 183, 860–874. [Google Scholar] [CrossRef] [PubMed]
- Dowell, J.; Minna, J.D.; Kirkpatrick, P. Erlotinib hydrochloride. Nat. Rev. Drug Discov. 2005, 4, 13–14. [Google Scholar] [CrossRef] [PubMed]
- Liu, W.; He, M.; Li, Y.; Peng, Z.; Wang, G. A review on synthetic chalcone derivatives as tubulin polymerisation inhibitors. J. Enzym. Inhib. Med. Chem. 2022, 37, 9–38. [Google Scholar] [CrossRef]
- Aits, S.; Jaattela, M.; Nylandsted, J. Methods for the quantification of lysosomal membrane permeabilization: A hallmark of lysosomal cell death. Methods Cell Biol. 2015, 126, 261–285. [Google Scholar] [CrossRef]
- Aits, S.; Kricker, J.; Liu, B.; Ellegaard, A.M.; Hamalisto, S.; Tvingsholm, S.; Corcelle-Termeau, E.; Hogh, S.; Farkas, T.; Holm Jonassen, A.; et al. Sensitive detection of lysosomal membrane permeabilization by lysosomal galectin puncta assay. Autophagy 2015, 11, 1408–1424. [Google Scholar] [CrossRef]
- Bock, F.J.; Tait, S.W.G. Mitochondria as multifaceted regulators of cell death. Nat. Rev. Mol. Cell Biol. 2020, 21, 85–100. [Google Scholar] [CrossRef]
- Dadsena, S.; Jenner, A.; García-Sáez, A.J. Mitochondrial outer membrane permeabilization at the single molecule level. Cell. Mol. Life Sci. 2021, 78, 3777–3790. [Google Scholar] [CrossRef]
IC50 Values (nM) | ||||||
---|---|---|---|---|---|---|
1 | 15 | 1 + 15 | 6a | 13 | 14 | |
Fadu | 1199 | 1880 | 362 | 389 | 770 | 658 |
Detroit 562 | 4035 | 3074 | 1488 | 673 | 810 | 1264 |
SCC-25 | 180 | 2777 | 173 | 725 | 1935 | 1444 |
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Murányi, J.; Duró, C.; Gurbi, B.; Móra, I.; Varga, A.; Németh, K.; Simon, J.; Csala, M.; Csámpai, A. Novel Erlotinib–Chalcone Hybrids Diminish Resistance in Head and Neck Cancer by Inducing Multiple Cell Death Mechanisms. Int. J. Mol. Sci. 2023, 24, 3456. https://doi.org/10.3390/ijms24043456
Murányi J, Duró C, Gurbi B, Móra I, Varga A, Németh K, Simon J, Csala M, Csámpai A. Novel Erlotinib–Chalcone Hybrids Diminish Resistance in Head and Neck Cancer by Inducing Multiple Cell Death Mechanisms. International Journal of Molecular Sciences. 2023; 24(4):3456. https://doi.org/10.3390/ijms24043456
Chicago/Turabian StyleMurányi, József, Cintia Duró, Bianka Gurbi, István Móra, Attila Varga, Krisztina Németh, József Simon, Miklós Csala, and Antal Csámpai. 2023. "Novel Erlotinib–Chalcone Hybrids Diminish Resistance in Head and Neck Cancer by Inducing Multiple Cell Death Mechanisms" International Journal of Molecular Sciences 24, no. 4: 3456. https://doi.org/10.3390/ijms24043456