Delineation of proapoptotic signaling of anthracene-shelled M2L4 metallacapsules and their synergistic activity with curcumin in cisplatin-sensitive and resistant tumor cell lines

  • Rositsa Mihaylova
  • Anife Ahmedova
  • Denitsa Momekova
  • Georgi MomekovEmail author
  • Nikolay Danchev


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.


Metallosupramolecules Synergism Curcumin Cisplatin resistance Collateral sensitivity Apoptosis 



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.

Compliance with ethical standards

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.

Ethical approval

This article does not contain any studies with human participants or animals performed by any of the authors.

Informed consent

For this type of study, formal consent is not required.


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© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Rositsa Mihaylova
    • 1
  • Anife Ahmedova
    • 2
  • Denitsa Momekova
    • 3
  • Georgi Momekov
    • 1
    Email author
  • Nikolay Danchev
    • 1
  1. 1.Department of Pharmacology, Pharmacotherapy and Toxicology, Faculty of PharmacyMedical University of SofiaSofiaBulgaria
  2. 2.Laboratory of Biocoordination and Bioanalytical Chemistry, Faculty of Chemistry and Pharmacy“St. Kliment Ohridski” Sofia UniversitySofiaBulgaria
  3. 3.Department of Pharmaceutical Technology and Biopharmaceutics, Faculty of PharmacyMedical University of SofiaSofiaBulgaria

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