Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on medication adherence

LIVE: Thursday 27th June 2024, 18:00-19:30 (CEST)
Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.
ADVANCED SEARCH
Log in
Top
BMC Cancer
Published in: BMC Cancer 1/2020

Open Access 01-12-2020 | Colorectal Cancer | Research article

A novel coordination complex of platinum (PT) induces cell death in colorectal cancer by altering redox balance and modulating MAPK pathway

Authors: Khayal Al-Khayal, Mansoor-Ali Vaali-Mohammed, Mohammed Elwatidy, Thamer Bin Traiki, Omar Al-Obeed, Mohammad Azam, Zahid Khan, Maha Abdulla, Rehan Ahmad

Published in: BMC Cancer | Issue 1/2020

Login to get access

Abstract

Background

Colorectal cancer (CRC) is a heterogeneous tumor having various genetic alterations. The current treatment options had limited impact on disease free survival due to therapeutic resistance. Novel anticancer agents are needed to treat CRC specifically metastatic colorectal cancer. A novel coordination complex of platinum, (salicylaldiminato)Pt(II) complex with dimethylpropylene linkage (PT) exhibited potential anti-cancer activity. In this study, we explored the molecular mechanism of PT-induced cell death in colorectal cancer.

Methods

Colony formation was evaluated using the clonogenic assay. Apoptosis, cell cycle analysis, reactive oxygen species, mitochondrial membrane potential and caspase-3/− 7 were assessed by flow cytometry. Glutathione level was detected by colorimetric assay. PT-induced alteration in pro-apoptotic/ anti-apoptotic proteins and other signaling pathways were investigated using western blotting. P38 downregulation was performed using siRNA.

Results

In the present study, we explored the molecular mechanism of PT-mediated inhibition of cell proliferation in colorectal cancer cells. PT significantly inhibited the colony formation in human colorectal cancer cell lines (HT-29, SW480 and SW620) by inducing apoptosis and necrosis. This platinum complex was shown to significantly increase the reactive oxygen species (ROS) generation, depletion of glutathione and reduced mitochondrial membrane potential in colorectal cancer cells. Exposure to PT resulted in the downregulation of anti-apoptotic proteins (Bcl2, BclxL, XIAP) and alteration in Cyclins expression. Furthermore, PT increased cytochrome c release into cytosol and enhanced PARP cleavage leading to activation of intrinsic apoptotic pathway. Moreover, pre-treatment with ROS scavenger N-acetylcysteine (NAC) attenuated apoptosis suggesting that PT-induced apoptosis was driven by oxidative stress. Additionally, we show that PT-induced apoptosis was mediated by activating p38 MAPK and inhibiting AKT pathways. This was demonstrated by using chemical inhibitor and siRNA against p38 kinase which blocked the cytochrome c release and apoptosis in colorectal cancer cells.

Conclusion

Collectively, our data demonstrates that the platinum complex (PT) exerts its anti-proliferative effect on CRC by ROS-mediated apoptosis and activating p38 MAPK pathway. Thus, our findings reveal a novel mechanism of action for PT on colorectal cancer cells and may have therapeutic implication.
Appendix
Available only for authorised users
Literature
1.
2.
3.
Fleming M, Ravula S, Tatishchev SF, Wang HL. Colorectal carcinoma: pathologic aspects. J Gastrointest Oncol. 2012;3:153–73.PubMedPubMedCentral
4.
Inamura K. Colorectal cancers: an update on their molecular pathology. Cancers (Basel). 2018;10:26.
5.
Jasperson KW, Tuohy TM, Neklason DW, Burt RW. Hereditary and familial colon cancer. Gastroenterology. 2010;138:2044–58.PubMed
6.
Graff RE, et al. Familial risk and heritability of colorectal cancer in the nordic twin study of cancer. Clin Gastroenterol Hepatol. 2017;15:1256–64.PubMedPubMedCentral
7.
8.
Folkesson J, Martling A, Kodeda K. Current considerations in colorectal cancer surgery. Colorectal Cancer. 2015;4:167–74.
9.
Gustavsson B, Carlsson G, Machover D, Petrelli N, Roth A, Schmoll HJ, Tveit KM, Gibson F. A review of the evolution of systemic chemotherapy in the management of colorectal cancer. Clin Colorectal Cancer. 2015;14:1–10.PubMed
10.
Dagoglu N, Mahadevan A, Nedea E, Poylin V, Nagle D. Stereotactic body radiotherapy (SBRT) reirradiation for pelvic recurrence from colorectal cancer. J Surg Oncol. 2015;111:478–82.PubMed
11.
Cunningham D, Atkin W, Lenz HJ, Lynch HT, Minsky B, Nordlinger B, Starling N. Colorectal cancer. Lancet. 2010;375:1030–47.PubMed
12.
Van der Jeught K, Xu H-C, Li Y-J, et al. Drug resistance and new therapies in colorectal cancer. World J Gastroenterol. 2018;24(34):3834–48.PubMedPubMedCentral
13.
Salonga D, Danenberg KD, Johnson M, Metzger R, Groshen S, Tsao-Wei DD, Lenz HJ, Leichman CG, Leichman L, Diasio RB, et al. Colorectal tumors responding to 5-fluorouracil have low gene expression levels of dihydropyrimidine dehydrogenase, thymidylate synthase, and thymidine phosphorylase. Clin Cancer Res. 2000;6:1322–7.PubMed
14.
Yaffee P, Osipov A, Tan C, Tuli R, Hendifar A. Review of systemic therapies for locally advanced and metastatic rectal cancer. J Gastrointest Oncol. 2015;6:185–200.PubMedPubMedCentral
15.
Siegel R, Desantis C, Jemal A. Colorectal cancer statistics, 2014. CA Cancer J Clin. 2014;64:104–17.PubMed
16.
Milczarek M, Rosinska S, Psurski M, Maciejewska M, Kutner A, Wietrzyk J. Combined colonic cancer treatment with vitamin D analogs and irinotecan or oxaliplatin. Anticancer Res. 2013;33(2):433–44.PubMed
17.
Imajo M, Tsuchiya Y, Nishida E. Regulatory mechanisms and functions of MAP kinase signaling pathways. IUBMB Life. 2006;58:312–7.PubMed
18.
Marshall MS. Ras target proteins in eukaryotic cells. FASEB J. 1995;9:1311–8.PubMed
19.
Qi M, Elion EA. MAP kinase pathways. J Cell Sci. 2005;118:3569–72.PubMed
20.
Azam M, Al-Resayes SI, Soliman SM, Trzesowska-Kruszynska A, Kruszynski R, Khan Z. A (salicylaldiminato)PT(II) complex with dimethylpropylene linkage:synthesis, structural characterization and antineoplastic activity. J Photochem Photobiol B Biol. 2017;176:150–6.
21.
22.
Ahmad R, Vaali-Mohammed M-A, Elwatidy M, et al. Induction of ROS-mediated cell death and activation of the JNK pathway by a sulfonamide derivate. Int J Mol Medicine. 2019;44(4):1552–6.
23.
Al-Khayal K, Alafeefy A, Vaali-Mohammed M-A, et al. Novel derivative of aminobenzenesulfonamide (3c) induces apoptosis in colorectal cancer cells through ROS generation and inhibits cell migration. BMC Cancer. 2017;17:4.PubMedPubMedCentral
24.
Buttke TM, Sandstrom PA. Oxidative stress as a mediator of apoptosis. Immunol Today. 1994;15:7–10.PubMed
25.
Fleury C, Mignotte B, Vayssiere JL. Mitochondrial reactive oxygen species in cell death signaling. Biochimie. 2002;84:131–41.PubMed
26.
Anderson ME. Glutathione: an overview of bio-synthesis and modulation. Chem Biol Interact. 1998;111–2:1–14.
27.
Hammond CL, Lee TK, Ballatori N. Novel roles for glutathione in gene expression, cell death, and mem-brane transport of organic solutes. J Hepatol. 2001;34:946–54.PubMed
28.
Chen X, Carystinos GD, Batist G. Potential for selective modulation of glutathione in cancer chemotherapy. Chem Biol Interact. 1998;111–2:263–75.
29.
Waterhouse NJ, Goldstein JC, Ahsen OV, et al. Cytochrome c maintains mitochondrial membrane potential and ATP generation after outer mitochondrial membrane permeabilization during apoptosis process. J Cell Biol. 2001;153:319–28.PubMedPubMedCentral
30.
Shamas-Din A, Kale J, Leber B, Andrews DW. Mechanism of action of Bcl-2 family proteins. Cold Spring Harb Perspect Biol. 2013;5:a008714.
31.
Casimiro MC, Crosariol M, Loro E, Li Z, Pestell RG. Cyclins and cell cycle control in cancer and disease. Genes Cancer. 2012;3:649–57.PubMedPubMedCentral
32.
Soldani C, Scovassi AI. Poly(ADP-ribose) polymerase-1 cleavage during apoptosis: an update. Apoptosis. 2002;7:321–8.PubMed
33.
34.
Raj, et al. Selective killing of cancer cells by a small molecule targeting the stress response to ROS. Nature. 2011;475:231–4.PubMedPubMedCentral
35.
Zikaki K, Aggeli IK, Gaitanaki C, Beis I. Curcumin induces theapoPTotic intrinsic pathway via upregulation od reactive oxygen species and JNKs in H9c2 cardiac myoblasts. Apoptosis. 2014;19:958–74.PubMed
36.
Chen L, Jiang K, Chen H, et al. Deguelin induces apoptosis in colorectal cancer cancer cells by activating the p38 MAPK pathway. Cancer Manag Res. 2019;11:95–105.PubMed
37.
Widmann C, Gibson S, Jarpe MB, Johnson GL. Mitogen-activated protein kinase: conservation of athree-kinase module from yeast to human. Physiol Rev. 1999;79:143–80.PubMed
38.
Chang L, Karin M. Mammalian MAP kinase signal-ling cascades. Nature. 2001;410:37–40.PubMed
39.
Yuan J, Rozengurt. PKD, PKD2 and p38 MAPK mediate Hsp27 Serine-82 phosphorylation induced ny neurotensin in Pancreatic Cancer PANC-1 cells. J Cell Biochem. 2008;103:648–62.PubMed
40.
Rosenberg B, VanCamp L, Trosko JE, Mansour VH. Platinum compounds: a new class of potent antitumor agents. Nature. 1969;222:385–6.PubMed
41.
Weiss RB, Christian MC. New cispalatin analogues in development. A review. Drugs. 1993;46:360–77.PubMed
42.
Gasser G, Ott I, Metzler-Nolte N. Organometallic anticancer compounds. J Med Chem. 2011;54:3–25.PubMed
43.
Stoehlmacher J. Prediction of efficacy and side effects of chemotherapy in colorectal cancer. Recent Results Cancer Res. 2007;176:81–8.PubMed
44.
Sava G, Bergamo A, Duson PJ. Metal-based antitumor drugs in the post-genomic era: what comes next? Dalton Trans. 2011;40:9069–75.PubMed
45.
Lazarevic T, Rilak A, Bugarcic ZD. Platinum, palladium, gold and ruthenium complexes as antitumor agents: current clinical uses, cytotoxicity studies and future perspectives. Euro J Med Chem. 2017;142:8–31.
46.
Silva TM, Andersson S, Sukumaran SK, et al. Norspermidine and novel Pd(II) and Pt(II) polynuclear complexes of norspermidine as potential antineoplastic agents against breast cancer. PLoS One. 2013;8:e55651.PubMedPubMedCentral
47.
Bostancioglu RB, Isik K, Genc H, et al. Studies on the cytotoxic, apoptotic and antitumoral effect of au (III) and Pt (II) complexes of 1, 10-phenanthroline on V79379A and A549 cell lines. J Enz Inhib Med Chem. 2011:1–9.
48.
49.
Tolan D, Gandin V, Morrison L, et al. Oxidative Stress Induced by Pt(IV) Pro-drugs Based on the Cisplatin Scaffold and Indole Carboxylic Acids in Axial Position. Sci Reports. 2016;6:29367.
50.
51.
52.
Wilmanski T, Zhou X, Zheng W, et al. Inhibition of pyruvate carboxylase by 1α,25-dihydroxyvitamin D promotes oxidative stress in early breast cancer progression. Cancer Lett. 2017;411:171–81.PubMedPubMedCentral
53.
Wilmanski T, Zhou X, Zheng W et al. Inhibition of pyruvate carboxylase by 1α,25-dihydroxyvitamin D promotes oxidative stress in early breast cancer progression. Cancer Letters 2017, 411, 171-181.
54.
Rahman F-U, Ali A, Duong H-Q, et al. ONS-donor ligand based Pt(II) complexes display extremely high anticancer potency through autophagic cell death pathway. Eur J Med Chem. 2019;164:546–61.PubMed
55.
Kowalski S, Wyrzykowski D, Hac S, et al. New oxidovanadium(IV) coordination complex containg 2-methylnitrilotriacetate ligands induces cell cycle arrest and autophagy in human pancreatic ductal adenocarcinoma cell lines. In J Mol Sci. 2019;20:261.
56.
Silva SLR, Bliza IRS, Dias RB, et al. Ru(II)-thymine complex causes DNA damage and apoptotic cell death in human colon carcinoma HCT116 cells mediated by JNK/p38/ERK1/2 via a p53-independent signaling. Sci Rep. 2019;9:11094.PubMedPubMedCentral
57.
Taniguchi K, Karin M. NFkB, inflammation, immunity and cancer: coming of age. Nat Rev Immunol. 2018;18:309–24.PubMed
58.
Sethi G, Ahn KS, Sung B, Aggarwal BB. Pinistol targets nuclear factor-kappaB activation pathway leading to inhibition of gene products associated with proliferation, apoptosis, invasion and angiogenesis. Mol Cancer Ther. 2008;7:1604–14.PubMed
59.
Wong ALA, Hirpara JL, Pervaiz S, Eu J-Q, Sethi G, Goh B-C. Do STAT3 inhibitors have potential in the future for cancer therapy. Expert Opin Investig Drugs. 2017;26:883–7.PubMed
60.
Zhu Y, Zhang M, Luo L, et al. NFkB hijacking theranostic Pt(II) complex in cancer therapy. Theranostics. 2019;9:2158–66.PubMedPubMedCentral
61.
Metadata
Title
A novel coordination complex of platinum (PT) induces cell death in colorectal cancer by altering redox balance and modulating MAPK pathway
Authors
Khayal Al-Khayal
Mansoor-Ali Vaali-Mohammed
Mohammed Elwatidy
Thamer Bin Traiki
Omar Al-Obeed
Mohammad Azam
Zahid Khan
Maha Abdulla
Rehan Ahmad
Publication date
01-12-2020
Publisher
BioMed Central
Published in
BMC Cancer / Issue 1/2020
Electronic ISSN: 1471-2407
DOI
https://doi.org/10.1186/s12885-020-07165-w

Other articles of this Issue 1/2020

BMC Cancer 1/2020 Go to the issue

Research article

Development and validation of an RNA binding protein-associated prognostic model for hepatocellular carcinoma

Research article

Right and left-sided colon cancers - specificity of molecular mechanisms in tumorigenesis and progression

Study protocol

Phase II study on first-line treatment of NIVolumab in combination with folfoxiri/bevacizumab in patients with Advanced COloRectal cancer RAS or BRAF mutated – NIVACOR trial (GOIRC-03-2018)

Research article

Modulation of SIRT3 expression through CDK4/6 enhances the anti-cancer effect of sorafenib in hepatocellular carcinoma cells

Research article

Comprehensive profiling of circular RNA expressions reveals potential diagnostic and prognostic biomarkers in multiple myeloma

Research article

Identification of immune cells and mRNA associated with prognosis of gastric cancer
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine
Image Credits