Since the introduction of cisplatin into clinical practice a few decades ago, the topic of metal-based drugs has expanded significantly. Recent examples emphasize on metallosupramolecules as an emerging class of compounds with diverse properties. They can trigger unique cellular events in malignant cells or serve as molecular hosts for various biologically active compounds, including anticancer agents. The anthracene-shelled M2L4 coordination nanocapsules under research have already proved very high anticancer potency with remarkable selectivity and lack of cross-resistance. In this study, we provide an oncopharmacological evaluation of the Pt(II)- and Pd(II)-clipped M2L4 nanocapsules; we report a thorough analysis of their synergistic effects in combined treatments with the pleiotropic anticancer agent curcumin. We examined changes in cellular expression of several apoptosis-related proteins in a panel of tumor cell lines with different chemosensitivity towards cisplatin, i.e. HT-29, HL-60 and its resistant strains HL-60/CDDP and HL-60/Dox, in order to assess the molecular mechanisms of their antitumor activity The results of the immunoassay concluded activation of the mitochondrial apoptotic pathway in all the screened tumor lines. A prevalent modulation of the extrinsic apoptotic signaling cascade was observed in the chemoresistant variants. Curcumin interactions of the tested compounds were estimated against the cisplatin-refractory cell line HT-29 via the Chou-Talalay method (CTM), whereby the palladium species yielded superior synergistic activity as compared to their platinum analogues.
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Boulikas T, Vougiouka M (2003) Cisplatin and platinum drugs at the molecular level (review). Oncol Rep 10:1663–1682. https://doi.org/10.3892/or.10.6.1663
Momekov G, Bakalova A, Karaivanova M (2005) Novel approaches towards development of non-classical platinum-based antineoplastic agents: Design of Platinum Complexes Characterized by an alternative DNA-binding pattern and/or tumor-targeted cytotoxicity. Curr Med Chem 12(19):2177–2191. https://doi.org/10.2174/0929867054864877
Galluzzi L, Vitale I, Michels J, Brenner C, Szabadkai G, Harel-Bellan A, Castedo M, Kroemer G (2014) Systems biology of cisplatin resistance: past, present and future. Cell Death Dis 5:e1257. https://doi.org/10.1038/cddis.2013.428
Galluzzi L, Senovilla L, Vitale I, Michels J, Martins I, Kepp O, Castedo M, Kroemer G (2012) Molecular mechanisms of cisplatin resistance. Oncogene 31(15):1869–1883. https://doi.org/10.1038/onc.2011.384
Shen DW, Pouliot LM, Hall MD, Gottesman MM (2012) Cisplatin resistance: a cellular self-defense mechanism resulting from multiple epigenetic and genetic changes. Pharmacol Rev 64(3):706–721. https://doi.org/10.1124/pr.111.005637
Sharom FJ (2014) Complex interplay between the P-glycoprotein multidrug efflux pump and the membrane: its role in modulating protein function. Front Oncol 4:41. https://doi.org/10.3389/fonc.2014.00041
Patel NR, Pattni BS, Abouzeid AH, Torchilin VP (2013) Nanopreparations to overcome multidrug resistance in cancer. Adv Drug Deliv Rev 65(13–14):1748–1762. https://doi.org/10.1016/j.addr.2013.08.004
Zinzi L, Capparelli E, Cantore M, Contino M, Leopoldo M, Colabufo NA (2014) Small and innovative molecules as new strategy to revert MDR. Front Oncol 4:2. https://doi.org/10.3389/fonc.2014.00002
Wu C-P, Hsieh C-H, Wu Y-S (2011) The emergence of drug transporter-mediated multidrug resistance to Cancer chemotherapy. Mol Pharm 8(6):1996–2011. https://doi.org/10.1021/mp200261n
Yamasaki M, Makino T, Masuzawa T, Kurokawa Y, Miyata H, Takiguchi S, Nakajima K, Fujiwara Y, Matsuura N, Mori M, Doki Y (2011) Role of multidrug resistance protein 2 (MRP2) in chemoresistance and clinical outcome in oesophageal squamous cell carcinoma. Br J Cancer 104(4):707–713. https://doi.org/10.1038/sj.bjc.6606071
Kilari D, Guancial E, Kim ES (2016) Role of copper transporters in platinum resistance. World J Clin Oncol 7(1):106–113. https://doi.org/10.5306/wjco.v7.i1.106
Zhu H, Luo H, Zhang W, Shen Z, Hu X, Zhu X (2016) Molecular mechanisms of cisplatin resistance in cervical cancer. Drug Des Devel Ther 10:1885–1895. https://doi.org/10.2147/DDDT.S106412
Matsuo K, Lin YG, Roman LD, Sood AK (2010) Overcoming platinum resistance in ovarian carcinoma. Expert Opin Investig Drugs 19(11):1339–1354. https://doi.org/10.1517/13543784.2010.515585
Wang X, Guo Z (2013) Targeting and delivery of platinum-based anticancer drugs. Chem Soc Rev 42(1):202–224. https://doi.org/10.1039/c2cs35259a
Zhou H, Wang G, Lu Y, Pan Z (2016) Bio-inspired cisplatin nanocarriers for osteosarcoma treatment. Biomater Sci 4(8):1212–1218. https://doi.org/10.1039/C6BM00331A
Piktel E, Niemirowicz K, Watek M, Wollny T, Deptula P, Bucki R (2016) Recent insights in nanotechnology-based drugs and formulations designed for effective anti-cancer therapy. J Nanobiotechnology 14(1):39. https://doi.org/10.1186/s12951-016-0193-x
Markman JL, Rekechenetskiy A, Holler E, Ljubimova JY (2013) Nanomedicine therapeutic approaches to overcome cancer drug resistance. Adv Drug Deliv Rev 65(13–14):1866–1879. https://doi.org/10.1016/j.addr.2013.09.019
Lewis JEM, Gavey EL, Cameron SA, Crowley JD (2012) Stimuli-responsive Pd2L4 metallosupramolecular cages: towards targeted cisplatin drug delivery. Chem Sci 3(3):778–784. https://doi.org/10.1039/c2sc00899h
Schmidt A, Hollering M, Drees M, Casini A, Kühn FE (2016) Supramolecular: Exo -functionalized palladium cages: fluorescent properties and biological activity. Dalton Trans 45(20):8556–8565. https://doi.org/10.1039/c6dt00654j
Therrien B (2012) Drug delivery by water-soluble organometallic cages. Top Curr Chem 319:35–55. https://doi.org/10.1007/128_2011_272
Ahmedova A, Momekova D, Yamashina M, Shestakova P, Momekov G, Akita M, Yoshizawa M (2016) Anticancer potencies of PtII-and PdII-linked M2L4 coordination capsules with improved selectivity. Chem Asian J 11(4):474–477
Ahmedova A, Mihaylova R, Momekova D, Shestakova P, Stoykova S, Zaharieva J, Yamashina M, Momekov G, Akita M, Yoshizawa M (2016) M2L4 coordination capsules with tunable anticancer activity upon guest encapsulation. Dalton Trans 45(33):13214–13221. https://doi.org/10.1039/C6DT01801G
Pinto AC, Moreira JN, Simões S (2011) Combination chemotherapy in Cancer: principles, evaluation and drug delivery strategies. Current Cancer treatment – novel beyond conventional approaches. InTech, Available from: http://www.intechopen.com/books/current-cancer-treatment-novel-beyond-conventional-approaches/combination-chemotherapy-in-cancer-principles-evaluation-and-drug-delivery-strategie. Accessed August 2018
Chou TC (2006) Theoretical basis, experimental design, and computerized simulation of synergism and antagonism in drug combination studies. Pharmacol Rev 58(3):621–681. https://doi.org/10.1124/pr.58.3.10
Chou TC, Talalay P (1984) Quantitative analysis of dose-effect relationships: the combined effects of multiple drugs or enzyme inhibitors. Adv Enzym Regul 22:27–55
Chou TC (2010) Drug combination studies and their synergy quantification using the Chou-Talalay method. Cancer Res 70(2):440–446. https://doi.org/10.1158/0008-5472.CAN-09-1947
Kishi N, Li Z, Yoza K, Akita M, Yoshizawa M (2011) An M2L4 molecular capsule with an anthracene Shell: encapsulation of large guests up to 1 nm. J Am Chem Soc 133(30):11438–11441. https://doi.org/10.1021/ja2037029
Yamashina M, Sei Y, Akita M, Yoshizawa M (2014) Safe storage of radical initiators within a polyaromatic nanocapsule. Nat Commun 5:4662. https://doi.org/10.1038/ncomms5662.
Zhelezova I, Momekov G, Кonstantinov S In vitro models of drug resistance in AML cell lines. In: Pajeva I, Argirova R, Bacvarov K, Boteva D, Burneva N (eds) Bulgarian-German scientific cooperation: past, present and future., Sofia, November 26–28, 2015. Humboldt Union in Bulgaria, pp 166–171
Assoc. Prof. Michito Yoshizawa, Dr. Masahiro Yamashina, and Prof. Munetaka Akita from Chemical Resources Laboratory of Tokyo Institute of Technology, Japan, are gratefully acknowledged for providing the coordination capsules, studied herein, and for their collaborative work in the past years. The National Science Fund of Bulgaria is gratefully acknowledged for the financial support (DFNI-B02/24).
The work was supported by the The National Science Fund of Bulgaria through Grant contract No. DFNI-B02/24.
Conflict of interest
Rositsa Mihaylova declares that she has no conflict of interest. Anife Ahmedova declares that she has no conflict of interest. Denitsa Momekova declares that she has no conflict of interest. Georgi Momekov declares that he has no conflict of interest. Nikolay Danchev declares that he has no conflict of interest.
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Mihaylova, R., Ahmedova, A., Momekova, D. et al. Delineation of proapoptotic signaling of anthracene-shelled M2L4 metallacapsules and their synergistic activity with curcumin in cisplatin-sensitive and resistant tumor cell lines. Invest New Drugs 37, 1117–1126 (2019). https://doi.org/10.1007/s10637-019-00738-y
- Cisplatin resistance
- Collateral sensitivity