Identification of 3-Aryl-1-benzotriazole-1-yl-acrylonitrile As a Microtubule-Targeting Agent (MTA) in Solid Tumors

Overview

Journal Int J Mol Sci

Publisher MDPI

Specialties Biochemistry
Chemistry
Molecular Biology

Date 2024 Jun 19

PMID 38891892

Authors

Stefano Zoroddu

Luca Sanna

Valentina Bordoni

Lyu Weidong

Sergio Domenico Gadau

Antonio Carta

David J Kelvin

Luigi Bagella

Affiliations

Soon will be listed here.

Abstract

Recently, a compound derived from recent scientific advances named has emerged as the focus of this research, the aim of which is to explore its potential impact on solid tumor cell lines. Using a combination of bioinformatics and biological assays, this study conducted an in-depth investigation of the effects of . The results of this study have substantial implications for cancer research and treatment. has shown remarkable efficacy in inhibiting the growth of several cancer cell lines, including those representing prostate carcinoma (PC3) and cervical carcinoma (HeLa). The high sensitivity of these cells, indicated by low IC values, underscores its potential as a promising chemotherapeutic agent. In addition, has revealed the ability to induce cell cycle arrest, particularly in the G2/M phase, a phenomenon with critical implications for tumor initiation and growth. By interfering with DNA replication in cancer cells, has shown the capacity to trigger cell death, offering a new avenue for cancer treatment. In addition, computational analyses have identified key genes affected by treatment, suggesting potential therapeutic targets. These genes are involved in critical biological processes, including cell cycle regulation, DNA replication and microtubule dynamics, all of which are central to cancer development and progression. In conclusion, this study highlights the different mechanisms of that inhibit cancer cell growth and alter the cell cycle. These promising results suggest the potential for more effective and less toxic anticancer therapies. Further in vivo validation and exploration of combination therapies are critical to improve cancer treatment outcomes.

References

Bian T, Zheng M, Jiang D, Liu J, Sun H, Li X . Prognostic biomarker TUBA1C is correlated to immune cell infiltration in the tumor microenvironment of lung adenocarcinoma. Cancer Cell Int. 2021; 21(1):144. PMC: 7923461. DOI: 10.1186/s12935-021-01849-4. View

Wang J, Li Y, Gao L, Yan F, Gao G, Li L . GSK-3β Inhibitor Alsterpaullone Attenuates MPP-Induced Cell Damage in a c-Myc-Dependent Manner in SH-SY5Y Cells. Front Cell Neurosci. 2018; 12:283. PMC: 6127625. DOI: 10.3389/fncel.2018.00283. View

Campanacci V, Urvoas A, Cantos-Fernandes S, Aumont-Nicaise M, Arteni A, Velours C . Insight into microtubule nucleation from tubulin-capping proteins. Proc Natl Acad Sci U S A. 2019; 116(20):9859-9864. PMC: 6525497. DOI: 10.1073/pnas.1813559116. View

Barreca M, Lang N, Tarantelli C, Spriano F, Barraja P, Bertoni F . Antibody-drug conjugates for lymphoma patients: preclinical and clinical evidences. Explor Target Antitumor Ther. 2023; 3(6):763-794. PMC: 9834635. DOI: 10.37349/etat.2022.00112. View

Dong C, Yang R, Li H, Ke K, Luo C, Yang F . Econazole nitrate inhibits PI3K activity and promotes apoptosis in lung cancer cells. Sci Rep. 2017; 7(1):17987. PMC: 5740072. DOI: 10.1038/s41598-017-18178-0. View

Maegawa S, Gopalakrishnan V . PLK inhibitors come of age in pediatric brain tumors. Neuro Oncol. 2022; 24(3):427-428. PMC: 8917393. DOI: 10.1093/neuonc/noab298. View

Jayathirtha M, Whitham D, Alwine S, Donnelly M, Neagu A, Darie C . Investigating the Function of Human Jumping Translocation Breakpoint Protein (hJTB) and Its Interacting Partners through In-Solution Proteomics of MCF7 Cells. Molecules. 2022; 27(23). PMC: 9740069. DOI: 10.3390/molecules27238301. View

Hao X, Bu W, Lv G, Xu L, Hou D, Wang J . Disrupted mitochondrial homeostasis coupled with mitotic arrest generates antineoplastic oxidative stress. Oncogene. 2021; 41(3):427-443. PMC: 8755538. DOI: 10.1038/s41388-021-02105-9. View

Riu F, Ibba R, Zoroddu S, Sestito S, Lai M, Piras S . Design, synthesis, and biological screening of a series of 4'-fluoro-benzotriazole-acrylonitrile derivatives as microtubule-destabilising agents (MDAs). J Enzyme Inhib Med Chem. 2022; 37(1):2223-2240. PMC: 9397482. DOI: 10.1080/14756366.2022.2111680. View

10.

Shuai W, Wang G, Zhang Y, Bu F, Zhang S, Miller D . Recent Progress on Tubulin Inhibitors with Dual Targeting Capabilities for Cancer Therapy. J Med Chem. 2021; 64(12):7963-7990. DOI: 10.1021/acs.jmedchem.1c00100. View

11.

Sutter A, Maaser K, Gerst B, Krahn A, Zeitz M, Scherubl H . Enhancement of peripheral benzodiazepine receptor ligand-induced apoptosis and cell cycle arrest of esophageal cancer cells by simultaneous inhibition of MAPK/ERK kinase. Biochem Pharmacol. 2004; 67(9):1701-10. DOI: 10.1016/j.bcp.2004.01.009. View

12.

Florian S, Mitchison T . Anti-Microtubule Drugs. Methods Mol Biol. 2016; 1413:403-21. DOI: 10.1007/978-1-4939-3542-0_25. View

13.

cermak V, Dostal V, Jelinek M, Libusova L, Kovar J, Rosel D . Microtubule-targeting agents and their impact on cancer treatment. Eur J Cell Biol. 2020; 99(4):151075. DOI: 10.1016/j.ejcb.2020.151075. View

14.

Risinger A, Li J, Bennett M, Rohena C, Peng J, Schriemer D . Taccalonolide binding to tubulin imparts microtubule stability and potent in vivo activity. Cancer Res. 2013; 73(22):6780-92. PMC: 3839246. DOI: 10.1158/0008-5472.CAN-13-1346. View

15.

Cushion T, Paciorkowski A, Pilz D, Mullins J, Seltzer L, Marion R . De novo mutations in the beta-tubulin gene TUBB2A cause simplified gyral patterning and infantile-onset epilepsy. Am J Hum Genet. 2014; 94(4):634-41. PMC: 3980418. DOI: 10.1016/j.ajhg.2014.03.009. View

16.

Carta A, Sanna P, Palomba M, Vargiu L, La Colla M, Loddo R . Synthesis and antiproliferative activity of 3-aryl-2-(1H-benzotriazol-1-yl)acrylonitriles. Part III. Eur J Med Chem. 2002; 37(11):891-900. DOI: 10.1016/s0223-5234(02)01411-3. View

17.

Kalous J, Jansova D, Susor A . Role of Cyclin-Dependent Kinase 1 in Translational Regulation in the M-Phase. Cells. 2020; 9(7). PMC: 7408968. DOI: 10.3390/cells9071568. View

18.

Zoroddu S, Sanna L, Bordoni V, Lyu W, Murineddu G, Pinna G . RNAseq Analysis of Novel 1,3,4-Oxadiazole Chalcogen Analogues Reveals Anti-Tubulin Properties on Cancer Cell Lines. Int J Mol Sci. 2023; 24(14). PMC: 10379353. DOI: 10.3390/ijms241411263. View

19.

Howard J, Hyman A . Microtubule polymerases and depolymerases. Curr Opin Cell Biol. 2006; 19(1):31-5. DOI: 10.1016/j.ceb.2006.12.009. View

20.

Zheng Y, Ikuno Y, Ohj M, Kusaka S, Jiang R, Cekic O . Platelet-derived growth factor receptor kinase inhibitor AG1295 and inhibition of experimental proliferative vitreoretinopathy. Jpn J Ophthalmol. 2003; 47(2):158-65. DOI: 10.1016/s0021-5155(02)00698-6. View