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Anti-Cancer Agents in Medicinal Chemistry

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ISSN (Print): 1871-5206
ISSN (Online): 1875-5992

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Research Article

Palladium (II) Complex Enhances ROS-Dependent Apoptotic Effects via Autophagy Inhibition and Disruption of Multiple Signaling Pathways in Colorectal Cancer Cells

Author(s): Seyma Aydinlik, Merve Erkisa, Ferda Ari, Serap Celikler and Engin Ulukaya*

Volume 21, Issue 10, 2021

Published on: 29 September, 2020

Page: [1284 - 1291] Pages: 8

DOI: 10.2174/1871520620666200929153804

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Abstract

Background: Inhibition of autophagy is reported to be a therapeutically effective strategy in overcoming resistance that is a deadly outcome in cancer. One of the most common reasons for chemo-resistance to treatment is the patients with tumors exhibiting a KRAS mutation, which occurs in approximately 40% of colorectal cancer patients.

Objective: Hence, we assessed whether a Palladium (Pd)(II) complex is a promising anticancer complex, compared to 5-fluorouracil in KRAS wt HT-29 and KRAS mutant HCT-15 cells.

Methods: HCT-15 and HT-29 cells were used for colorectal cancer and Chloroquine (CQ) was used as an inhibitor of autophagy. In this context, cells were treated with Pd(II) complex and 5-FU in combination with CQ for 48h and cell viability was measured by SRB assay. Cell death mode was examined with M30 and M65 ELISA assays, using annexin V/propidium iodide. Autophagy was determined by Acridine Orange (AO) staining. Furthermore, the expressions of various autophagy and apoptosis-related proteins were evaluated with Western blotting. Luminex assay and the level of Reactive Oxygen Species (ROS) were examined.

Results: Cell viability was found to decrease in a dose-dependent manner and CQ enhanced cytotoxic effect in Pd(II) and 5-FU treated cells in colorectal cancer cells. Our data showed that inhibition of autophagic flux significantly increased intrinsic apoptosis through the activation of ROS. We showed that combinatorial treatment with CQ induced apoptosis via the caspase-dependent mitochondrial pathway. Luminex analysis revealed that the combination resulted in a down-regulation of NF-κB/AKT/CREB signaling pathways in both cell lines, however, decreased Erk1/2 protein expression was only observed after treatment with CQ combination in HCT-15 cells.

Conclusion: We suggest that the inhibition of autophagy along with Pd(II) and 5-FU treatment has a synergistic effect on KRAS-mutant colorectal cancer cells. Autophagy inhibition by CQ promotes apoptosis via blockade of the NF-κB/AKT/CREB and activation of ROS.

Keywords: Apoptosis, autophagy, metal-based compounds, ROS, colorectal cancer, chloroquine.

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[1]
Burada, F.; Nicoli, E.R.; Ciurea, M.E.; Uscatu, D.C.; Ioana, M.; Gheonea, D.I. Autophagy in colorectal cancer: An important switch from physiology to pathology. World J. Gastrointest. Oncol., 2015, 7(11), 271-284.
[http://dx.doi.org/10.4251/wjgo.v7.i11.271] [PMID: 26600927]
[2]
Zhou, H.; Yuan, M.; Yu, Q.; Zhou, X.; Min, W.; Gao, D. Autophagy regulation and its role in gastric cancer and colorectal cancer. Cancer Biomark., 2016, 17(1), 1-10.
[http://dx.doi.org/10.3233/CBM-160613] [PMID: 27314289]
[3]
Li, J.; Hou, N.; Faried, A.; Tsutsumi, S.; Kuwano, H. Inhibition of autophagy augments 5-fluorouracil chemotherapy in human colon cancer in vitro and in vivo model. Eur. J. Cancer, 2010, 46(10), 1900-1909.
[http://dx.doi.org/10.1016/j.ejca.2010.02.021] [PMID: 20231086]
[4]
Yang, P.M.; Liu, Y.L.; Lin, Y.C.; Shun, C.T.; Wu, M.S.; Chen, C.C. Inhibition of autophagy enhances anticancer effects of atorvastatin in digestive malignancies. Cancer Res., 2010, 70(19), 7699-7709.
[http://dx.doi.org/10.1158/0008-5472.CAN-10-1626] [PMID: 20876807]
[5]
Liu, L.; Zhao, W.M.; Yang, X.H.; Sun, Z.Q.; Jin, H.Z.; Lei, C.; Jin, B.; Wang, H.J. Effect of inhibiting Beclin-1 expression on autophagy, proliferation and apoptosis in colorectal cancer. Oncol. Lett., 2017, 14(4), 4319-4324.
[http://dx.doi.org/10.3892/ol.2017.6687] [PMID: 28989537]
[6]
Giantonio, B.J.; Catalano, P.J.; Meropol, N.J.; O’Dwyer, P.J.; Mitchell, E.P.; Alberts, S.R.; Schwartz, M.A.; Benson, A.B. III Eastern Cooperative Oncology Group Study E3200. Bevacizumab in combination with oxaliplatin, fluorouracil, and leucovorin (FOLFOX4) for previously treated metastatic colorectal cancer: Results from the Eastern Cooperative Oncology Group Study E3200. J. Clin. Oncol., 2007, 25(12), 1539-1544.
[http://dx.doi.org/10.1200/JCO.2006.09.6305] [PMID: 17442997]
[7]
Tournigand, C.; André, T.; Achille, E.; Lledo, G.; Flesh, M.; Mery-Mignard, D.; Quinaux, E.; Couteau, C.; Buyse, M.; Ganem, G.; Landi, B.; Colin, P.; Louvet, C.; de Gramont, A. FOLFIRI followed by FOLFOX6 or the reverse sequence in advanced colorectal cancer: A randomized GERCOR study. J. Clin. Oncol., 2004, 22(2), 229-237.
[http://dx.doi.org/10.1200/JCO.2004.05.113] [PMID: 14657227]
[8]
Welch, S.; Spithoff, K.; Rumble, R.B.; Maroun, J. Gastrointestinal Cancer Disease Site Group. Bevacizumab combined with chemotherapy for patients with advanced colorectal cancer: A systematic review. Ann. Oncol., 2010, 21(6), 1152-1162.
[http://dx.doi.org/10.1093/annonc/mdp533] [PMID: 19942597]
[9]
Karami, K.; Alinaghi, M.; Amirghofran, Z.; Lipkowski, J.; Momtazi-Borojeni, A.A. A saccharinate-bridged palladacyclic dimer with a Pd-Pd bond: Experimental and molecular docking studies of the interaction with DNA and BSA and in vitro cytotoxicity against human cancer cell lines. New J. Chem., 2018, 42(1), 574-586.
[http://dx.doi.org/10.1039/C7NJ03138F]
[10]
Yilmaz, V.T.; Icsel, C.; Turgut, O.R.; Aygun, M.; Erkisa, M.; Turkdemir, M.H.; Ulukaya, E. Synthesis, structures and anticancer potentials of platinum(II) saccharinate complexes of tertiary phosphines with phenyl and cyclohexyl groups targeting mitochondria and DNA. Eur. J. Med. Chem., 2018, 155, 609-622.
[http://dx.doi.org/10.1016/j.ejmech.2018.06.035] [PMID: 29920455]
[11]
Abu-Surrah, A.S.; Abu Safieh, K.A.; Ahmad, I.M.; Abdalla, M.Y.; Ayoub, M.T.; Qaroush, A.K.; Abu-Mahtheieh, A.M. New palladium(II) complexes bearing pyrazole-based Schiff base ligands: Synthesis, characterization and cytotoxicity. Eur. J. Med. Chem., 2010, 45(2), 471-475.
[http://dx.doi.org/10.1016/j.ejmech.2009.10.029] [PMID: 19913953]
[12]
Ari, F.; Aztopal, N.; Icsel, C.; Yilmaz, V.T.; Guney, E.; Buyukgungor, O.; Ulukaya, E. Synthesis, structural characterization and cell death-inducing effect of novel palladium(II) and platinum(II) saccharinate complexes with 2-(hydroxymethyl)pyridine and 2-(2-hydroxyethyl)pyridine on cancer cells in vitro. Bioorg. Med. Chem., 2013, 21(21), 6427-6434.
[http://dx.doi.org/10.1016/j.bmc.2013.08.050] [PMID: 24054490]
[13]
Weiss, J.T.; Fraser, C.; Rubio-Ruiz, B.; Myers, S.H.; Crispin, R.; Dawson, J.C.; Brunton, V.G.; Patton, E.E.; Carragher, N.O.; Unciti-Broceta, A. N-alkynyl derivatives of 5-fluorouracil: Susceptibility to palladium-mediated dealkylation and toxigenicity in cancer cell culture. Front Chem., 2014, 2(JUL), 56.
[http://dx.doi.org/10.3389/fchem.2014.00056] [PMID: 25121087]
[14]
Icsel, C.; Yilmaz, V.T.; Kaya, Y.; Durmus, S.; Sarimahmut, M.; Buyukgungor, O.; Ulukaya, E. Cationic Pd(II)/Pt(II) 5,5-diethylbarbiturate complexes with bis(2-pyridylmethyl)amine and terpyridine: Synthesis, structures,DNA/BSA interactions, intracellular distribution, cytotoxic activity and induction of apoptosis. J. Inorg. Biochem., 2015, 152, 38-52.
[http://dx.doi.org/10.1016/j.jinorgbio.2015.08.026] [PMID: 26339715]
[15]
Aydinlik, S.; Dere, E.; Ulukaya, E. Induction of autophagy enhances apoptotic cell death via epidermal growth factor receptor inhibition by canertinib in cervical cancer cells. Biochim. Biophys. Acta, Gen. Subj., 2019, 1863(5), 903-916.
[http://dx.doi.org/10.1016/j.bbagen.2019.02.014] [PMID: 30825616]
[16]
Cevatemre, B.; Ulukaya, E.; Sarimahmut, M.; Oral, A.Y.; Frame, F.M. The M30 assay does not detect apoptosis in epithelial-derived cancer cells expressing low levels of cytokeratin 18. Tumour Biol., 2015, 36(9), 6857-6865.
[http://dx.doi.org/10.1007/s13277-015-3367-5] [PMID: 25846732]
[17]
Aydinlik, S.; Erkisa, M.; Cevatemre, B.; Sarimahmut, M.; Dere, E.; Ari, F.; Ulukaya, E. Enhanced cytotoxic activity of doxorubicin through the inhibition of autophagy in triple negative breast cancer cell line. Biochim. Biophys. Acta, Gen. Subj., 2017, 1861(2), 49-57.
[http://dx.doi.org/10.1016/j.bbagen.2016.11.013] [PMID: 27842219]
[18]
Lang, W.H.; Sandoval, J.A. Detection of PI3K inhibition in human neuroblastoma using multiplex luminex bead immunoassay: A targeted approach for pathway analysis. J. Biomol. Screen., 2014, 19(9), 1235-1245.
[http://dx.doi.org/10.1177/1087057114545650] [PMID: 25092063]
[19]
Cai, Y.; Cai, J.; Ma, Q.; Xu, Y.; Zou, J.; Xu, L.; Wang, D.; Guo, X. Chloroquine affects autophagy to achieve an anticancer effect in EC109 esophageal carcinoma cells in vitro. Oncol. Lett., 2018, 15(1), 1143-1148.
[http://dx.doi.org/10.3892/ol.2017.7415] [PMID: 29422973]
[20]
Wu, Y.Y.; Zheng, B.R.; Chen, W.Z.; Guo, M.S.; Huang, Y.H.; Zhang, Y. Expression and role of autophagy related protein p62 and LC3 in the retina in a rat model of acute ocular hypertension. Int. J. Ophthalmol., 2020, 13(1), 21-28.
[http://dx.doi.org/10.18240/ijo.2020.01.04] [PMID: 31956566]
[21]
Myeku, N.; Figueiredo-Pereira, M.E. Dynamics of the degradation of ubiquitinated proteins by proteasomes and autophagy: Association with sequestosome 1/p62. J. Biol. Chem., 2011, 286(25), 22426-22440.
[http://dx.doi.org/10.1074/jbc.M110.149252] [PMID: 21536669]
[22]
Devenport, S.N.; Shah, Y.M. Functions and implications of autophagy in colon cancer. Cells, 2019, 8(11), 1349.
[http://dx.doi.org/10.3390/cells8111349] [PMID: 31671556]
[23]
Bijnsdorp, I.V.; Peters, G.J.; Temmink, O.H.; Fukushima, M.; Kruyt, F.A. Differential activation of cell death and autophagy results in an increased cytotoxic potential for trifluorothymidine compared to 5-fluorouracil in colon cancer cells. Int. J. Cancer, 2010, 126(10), 2457-2468.
[http://dx.doi.org/10.1002/ijc.24943] [PMID: 19816940]
[24]
Volarevic, V.; Vujic, J.M.; Milovanovic, M.; Kanjevac, T.; Volarevic, A.; Trifunovic, S.R.; Arsenijevic, N. Cytotoxic effects of palladium (II) and platinum (II) complexes with O,O′-dialkyl esters of (S,S)-ethylenediamine-N,N′-di-2-(4-methyl) pentanoic acid on human colon cancer cell lines. J. BUON, 2013, 18(1), 131-137.
[PMID: 23613398]
[25]
Schonewolf, C.A.; Mehta, M.; Schiff, D.; Wu, H.; Haffty, B.G.; Karantza, V.; Jabbour, S.K. Autophagy inhibition by chloroquine sensitizes HT-29 colorectal cancer cells to concurrent chemoradiation. World J. Gastrointest. Oncol., 2014, 6(3), 74-82.
[http://dx.doi.org/10.4251/wjgo.v6.i3.74] [PMID: 24653797]
[26]
Li, J.; Hou, N.; Faried, A.; Tsutsumi, S.; Takeuchi, T.; Kuwano, H. Inhibition of autophagy by 3-MA enhances the effect of 5-FU-induced apoptosis in colon cancer cells. Ann. Surg. Oncol., 2009, 16(3), 761-771.
[http://dx.doi.org/10.1245/s10434-008-0260-0] [PMID: 19116755]
[27]
Sasaki, K.; Tsuno, N.H.; Sunami, E.; Kawai, K.; Hongo, K.; Hiyoshi, M.; Kaneko, M.; Murono, K.; Tada, N.; Nirei, T.; Takahashi, K.; Kitayama, J. Resistance of colon cancer to 5-fluorouracil may be overcome by combination with chloroquine, an in vivo study. Anticancer Drugs, 2012, 23(7), 675-682.
[http://dx.doi.org/10.1097/CAD.0b013e328353f8c7] [PMID: 22561420]
[28]
Ulukaya, E.; Frame, F.M.; Cevatemre, B.; Pellacani, D.; Walker, H.; Mann, V.M.; Simms, M.S.; Stower, M.J.; Yilmaz, V.T.; Maitland, N.J. Differential cytotoxic activity of a novel palladium-based compound on prostate cell lines, primary prostate epithelial cells and prostate stem cells. PLoS One, 2013, 8(5), e64278.
[http://dx.doi.org/10.1371/journal.pone.0064278] [PMID: 23675532]
[29]
Giménez-Xavier, P.; Francisco, R.; Platini, F.; Pérez, R.; Ambrosio, S. LC3-I conversion to LC3-II does not necessarily result in complete autophagy. Int. J. Mol. Med., 2008, 22(6), 781-785.
[http://dx.doi.org/10.3892/ijmm_00000085] [PMID: 19020776]
[30]
Li, X.; Yan, J.; Wang, L.; Xiao, F.; Yang, Y.; Guo, X.; Wang, H. Beclin1 inhibition promotes autophagy and decreases gemcitabine-induced apoptosis in Miapaca2 pancreatic cancer cells. Cancer Cell Int., 2013, 13(1), 26.
[http://dx.doi.org/10.1186/1475-2867-13-26] [PMID: 23497401]
[31]
Yan, J.; Dou, X.; Zhou, J.; Xiong, Y.; Mo, L.; Li, L.; Lei, Y. Tubeimoside-I sensitizes colorectal cancer cells to chemotherapy by inducing ROS-mediated impaired autophagolysosomes accumulation. J. Exp. Clin. Cancer Res., 2019, 38(1), 353.
[http://dx.doi.org/10.1186/s13046-019-1355-0] [PMID: 31412953]
[32]
Li, Q.; Yin, Y.; Zheng, Y.; Chen, F.; Jin, P. Inhibition of autophagy promoted high glucose/ROS-mediated apoptosis in ADSCs. Stem Cell Res. Ther., 2018, 9(1), 289.
[http://dx.doi.org/10.1186/s13287-018-1029-4] [PMID: 30359319]
[33]
Huang, Y.; Yang, L.; Lin, Y.; Chang, X.; Wu, H.; Chen, Y. Prognostic value of non-invasive serum Cytokeratin 18 detection in gastrointestinal cancer: A meta-analysis. J. Cancer, 2019, 10(20), 4814-4823.
[http://dx.doi.org/10.7150/jca.31408] [PMID: 31598152]
[34]
Son, Y.; Cheong, Y-K.; Kim, N-H.; Chung, H-T.; Kang, D.G.; Pae, H-O. Mitogen-activated protein kinases and reactive oxygen species: How can ROS activate MAPK pathways? J. Signal Transduct., 2011, 2011, 792639.
[http://dx.doi.org/10.1155/2011/792639] [PMID: 21637379]
[35]
Zhang, J.; Wang, X.; Vikash, V.; Ye, Q.; Wu, D.; Liu, Y.; Dong, W. ROS and ROS-Mediated Cellular Signaling. Oxid. Med. Cell. Longev., 2016.
[http://dx.doi.org/10.1155/2016/4350965]
[36]
de la Cruz-Morcillo, M.A.; Valero, M.L.L.; Callejas-Valera, J.L.; Arias-González, L.; Melgar-Rojas, P.; Galán-Moya, E.M.; García-Gil, E.; García-Cano, J.; Sánchez-Prieto, R. P38MAPK is a major determinant of the balance between apoptosis and autophagy triggered by 5-fluorouracil: Implication in resistance. Oncogene, 2012, 31(9), 1073-1085.
[http://dx.doi.org/10.1038/onc.2011.321] [PMID: 21841826]
[37]
Huang, R.H.; Quan, Y.J.; Chen, J.H.; Wang, T.F.; Xu, M.; Ye, M.; Yuan, H.; Zhang, C.J.; Liu, X.J.; Min, Z.J. Osteopontin promotes cell migration and invasion, and inhibits apoptosis and autophagy in colorectal cancer by activating the p38 MAPK signaling pathway. Cell. Physiol. Biochem., 2017, 41(5), 1851-1864.
[http://dx.doi.org/10.1159/000471933] [PMID: 28376477]
[38]
Lee, Y.; Na, J.; Lee, M.S.; Cha, E.Y.; Sul, J.Y.; Park, J.B.; Lee, J.S. Combination of pristimerin and paclitaxel additively induces autophagy in human breast cancer cells via ERK1/2 regulation. Mol. Med. Rep., 2018, 18(5), 4281-4288.
[http://dx.doi.org/10.3892/mmr.2018.9488] [PMID: 30221728]
[39]
Recktenwald, C.V.; Mendler, S.; Lichtenfels, R.; Kellner, R.; Seliger, B. Influence of Ki-ras-driven oncogenic transformation on the protein network of murine fibroblasts. Proteomics, 2007, 7(3), 385-398.
[http://dx.doi.org/10.1002/pmic.200600506] [PMID: 17211828]
[40]
Lin, G.; Zheng, X.W.; Li, C.; Chen, Q.; Ye, Y.B. KRAS mutation and NF-κB activation indicates tolerance of chemotherapy and poor prognosis in colorectal cancer. Dig. Dis. Sci., 2012, 57(9), 2325-2333.
[http://dx.doi.org/10.1007/s10620-012-2172-x] [PMID: 22526587]
[41]
Liu, S.; Wu, D.; Li, L.; Sun, X.; Xie, W.; Li, X. NF-κB activation was involved in reactive oxygen species-mediated apoptosis and autophagy in 1-oxoeudesm-11(13)-eno-12,8α-lactone-treated human lung cancer cells. Arch. Pharm. Res., 2014, 37(8), 1039-1052.
[http://dx.doi.org/10.1007/s12272-013-0270-8] [PMID: 24194260]
[42]
Wang, W.; McLeod, H.L.; Cassidy, J. Disulfiram-mediated inhibition of NF-kappaB activity enhances cytotoxicity of 5-fluorouracil in human colorectal cancer cell lines. Int. J. Cancer, 2003, 104(4), 504-511.
[http://dx.doi.org/10.1002/ijc.10972] [PMID: 12584750]
[43]
Voboril, R.; Hochwald, S.N.; Li, J.; Brank, A.; Weberova, J.; Wessels, F.; Moldawer, L.L.; Camp, E.R.; MacKay, S.L.D. Inhibition of NF-kappa B augments sensitivity to 5-fluorouracil/folinic acid in colon cancer. J. Surg. Res., 2004, 120(2), 178-188.
[http://dx.doi.org/10.1016/j.jss.2003.11.023] [PMID: 15234211]
[44]
Chang, C.T.; Ho, T.Y.; Lin, H.; Liang, J.A.; Huang, H.C.; Li, C.C.; Lo, H.Y.; Wu, S.L.; Huang, Y.F.; Hsiang, C.Y. 5-Fluorouracil induced intestinal mucositis via nuclear factor-κB activation by transcriptomic analysis and in vivo bioluminescence imaging. PLoS One, 2012, 7(3), e31808.
[http://dx.doi.org/10.1371/journal.pone.0031808] [PMID: 22412841]
[45]
Wang, J.; Whiteman, M.W.; Lian, H.; Wang, G.; Singh, A.; Huang, D.; Denmark, T. A non-canonical MEK/ERK signaling pathway regulates autophagy via regulating Beclin 1. J. Biol. Chem., 2009, 284(32), 21412-21424.
[http://dx.doi.org/10.1074/jbc.M109.026013] [PMID: 19520853]

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