Antimigratory Effect of Lipophilic Cations Derived from Gallic and Gentisic Acid and Synergistic Effect with 5-Fluorouracil on Metastatic Colorectal Cancer Cells: A New Synthesis Route

Overview

Journal Cancers (Basel)

Publisher MDPI

Specialty Oncology

Date 2024 Sep 14

PMID 39272835

Authors

Cristian Suarez-Rozas

Jose Antonio Jara

Gonzalo Cortes

Diego Rojas

Gabriel Araya-Valdes

Alfredo Molina-Berrios

Fabiola Gonzalez-Herrera

Sebastian Fuentes-Retamal

Pablo Aranguiz-Urroz

Paola Rossana Campodonico

Juan Diego Maya

Raul Vivar

Mabel Catalan

Affiliations

Soon will be listed here.

Abstract

Colorectal cancer (CRC) is the third leading cause of cancer deaths in the world. Standard drugs currently used for the treatment of advanced CRC-such as 5-fluorouracil (5FU)-remain unsatisfactory in their results due to their high toxicity, high resistance, and adverse effects. In recent years, mitochondria have become an attractive target for cancer therapy due to higher transmembrane mitochondrial potential. We synthesized gallic acid derivatives linked to a ten-carbon aliphatic chain associated with triphenylphosphonium (TPPC), a lipophilic cationic molecule that induces the uncoupling of the electron transport chain (ETC). Other derivatives, such as gentisic acid (GA-TPPC), have the same effects on colorectal cancer cells. Although part of our group had previously reported preparing these structures by a convergent synthesis route, including their application via flow chemistry, there was no precedent for a new methodology for preparing these compounds. In this scenario, this study aims to develop a new linear synthesis strategy involving an essential step of Steglich esterification under mild conditions (open flask) and a high degree of reproducibility. Moreover, the study seeks to associate GA-TPPC with 5FU to evaluate synergistic antineoplastic effects. In addition, we assess the antimigratory effect of GA-TPPC and TPPC using human and mouse metastatic CRC cell lines. The results show a new and efficient synthesis route of these compounds, having synergistic effects in combination with 5FU, increasing apoptosis and enhancing cytotoxic properties. Additionally, the results show a robust antimigratory effect of GATPPC10 and TPPC, reducing the activation pathways linked to tumor progression and reducing the expression of VEGF and MMP-2 and MMP-9, common biomarkers of advanced CRC. Moreover, TPPC and GA-TPPC increase the activity of metabolic signaling pathways through AMPK activation. The data allow us to conclude that these compounds can be used for in vivo evaluations and are a promising alternative associated with conventional therapies for advanced colorectal cancer. Additionally, the reported intermediates of the new synthesis route could give rise to analog compounds with improved therapeutic activity.

References

Welch D, Hurst D . Defining the Hallmarks of Metastasis. Cancer Res. 2019; 79(12):3011-3027. PMC: 6571042. DOI: 10.1158/0008-5472.CAN-19-0458. View

Zhao W, Sachsenmeier K, Zhang L, Sult E, Hollingsworth R, Yang H . A New Bliss Independence Model to Analyze Drug Combination Data. J Biomol Screen. 2014; 19(5):817-21. DOI: 10.1177/1087057114521867. View

Kciuk M, Gielecinska A, Budzinska A, Mojzych M, Kontek R . Metastasis and MAPK Pathways. Int J Mol Sci. 2022; 23(7). PMC: 8998814. DOI: 10.3390/ijms23073847. View

Peredo-Silva L, Fuentes-Retamal S, Sandoval-Acuna C, Pavani M, Maya J, Castro-Castillo V . Derivatives of alkyl gallate triphenylphosphonium exhibit antitumor activity in a syngeneic murine model of mammary adenocarcinoma. Toxicol Appl Pharmacol. 2017; 329:334-346. DOI: 10.1016/j.taap.2017.06.017. View

Bayat Mokhtari R, Homayouni T, Baluch N, Morgatskaya E, Kumar S, Das B . Combination therapy in combating cancer. Oncotarget. 2017; 8(23):38022-38043. PMC: 5514969. DOI: 10.18632/oncotarget.16723. View

Zhang Y, Wang Y, Zhang B, Li P, Zhao Y . Methods and biomarkers for early detection, prediction, and diagnosis of colorectal cancer. Biomed Pharmacother. 2023; 163:114786. DOI: 10.1016/j.biopha.2023.114786. View

Arnold C, Demuth P, Seiwert N, Wittmann S, Boengler K, Rasenberger B . The Mitochondrial Disruptor Devimistat (CPI-613) Synergizes with Genotoxic Anticancer Drugs in Colorectal Cancer Therapy in a Bim-Dependent Manner. Mol Cancer Ther. 2021; 21(1):100-112. DOI: 10.1158/1535-7163.MCT-21-0393. View

Leanza L, Romio M, Becker K, Azzolini M, Trentin L, Manago A . Direct Pharmacological Targeting of a Mitochondrial Ion Channel Selectively Kills Tumor Cells In Vivo. Cancer Cell. 2017; 31(4):516-531.e10. DOI: 10.1016/j.ccell.2017.03.003. View

Chun S, Johnson C, Washburn J, Cruz-Correa M, Dang D, Dang L . Oncogenic KRAS modulates mitochondrial metabolism in human colon cancer cells by inducing HIF-1α and HIF-2α target genes. Mol Cancer. 2010; 9:293. PMC: 2999617. DOI: 10.1186/1476-4598-9-293. View

10.

Rajamalli P, Prasad E . Low molecular weight fluorescent organogel for fluoride ion detection. Org Lett. 2011; 13(14):3714-7. DOI: 10.1021/ol201325j. View

11.

Sugiura K, Okabayashi K, Seishima R, Ishida T, Shigeta K, Tsuruta M . Metformin inhibits the development and metastasis of colorectal cancer. Med Oncol. 2022; 39(9):136. DOI: 10.1007/s12032-022-01722-y. View

12.

Vogel J, Felder S, Bhama A, Hawkins A, Langenfeld S, Shaffer V . The American Society of Colon and Rectal Surgeons Clinical Practice Guidelines for the Management of Colon Cancer. Dis Colon Rectum. 2021; 65(2):148-177. DOI: 10.1097/DCR.0000000000002323. View

13.

Kamran S, Sinniah A, Chik Z, Alshawsh M . Diosmetin Exerts Synergistic Effects in Combination with 5-Fluorouracil in Colorectal Cancer Cells. Biomedicines. 2022; 10(3). PMC: 8945009. DOI: 10.3390/biomedicines10030531. View

14.

Yuan J, Dong X, Yap J, Hu J . The MAPK and AMPK signalings: interplay and implication in targeted cancer therapy. J Hematol Oncol. 2020; 13(1):113. PMC: 7433213. DOI: 10.1186/s13045-020-00949-4. View

15.

Siegel R, Miller K, Jemal A . Colorectal Cancer Mortality Rates in Adults Aged 20 to 54 Years in the United States, 1970-2014. JAMA. 2017; 318(6):572-574. PMC: 5817468. DOI: 10.1001/jama.2017.7630. View

16.

Blondy S, David V, Verdier M, Mathonnet M, Perraud A, Christou N . 5-Fluorouracil resistance mechanisms in colorectal cancer: From classical pathways to promising processes. Cancer Sci. 2020; 111(9):3142-3154. PMC: 7469786. DOI: 10.1111/cas.14532. View

17.

Siegel R, Fedewa S, Anderson W, Miller K, Ma J, Rosenberg P . Colorectal Cancer Incidence Patterns in the United States, 1974-2013. J Natl Cancer Inst. 2017; 109(8). PMC: 6059239. DOI: 10.1093/jnci/djw322. View

18.

Jara J, Rojas D, Castro-Castillo V, Fuentes-Retamal S, Sandoval-Acuna C, Parra E . Novel benzoate-lipophilic cations selectively induce cell death in human colorectal cancer cell lines. Toxicol In Vitro. 2020; 65:104814. DOI: 10.1016/j.tiv.2020.104814. View

19.

Marini M, Titiz M, Souza Monteiro de Araujo D, Geppetti P, Nassini R, De Logu F . TRP Channels in Cancer: Signaling Mechanisms and Translational Approaches. Biomolecules. 2023; 13(10). PMC: 10605459. DOI: 10.3390/biom13101557. View

20.

Li Q, Wei L, Lin S, Chen Y, Lin J, Peng J . Synergistic effect of kaempferol and 5‑fluorouracil on the growth of colorectal cancer cells by regulating the PI3K/Akt signaling pathway. Mol Med Rep. 2019; 20(1):728-734. DOI: 10.3892/mmr.2019.10296. View