PRECLINICAL STUDIES Delineation of proapoptotic signaling of anthracene-shelled M 2 L 4 metallacapsules and their synergistic activity with curcumin in cisplatin-sensitive and resistant tumor cell lines Rositsa Mihaylova 1 & Anife Ahmedova 2 & Denitsa Momekova 3 & Georgi Momekov 1 & Nikolay Danchev 1 Received: 7 December 2018 /Accepted: 31 January 2019 # Springer Science+Business Media, LLC, part of Springer Nature 2019 Summary Since the introduction of cisplatin into clinical practice a few decades ago, the topic of metal-based drugs has expanded signifi- cantly. 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 M 2 L 4 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 M 2 L 4 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. Keywords Metallosupramolecules . Synergism . Curcumin . Cisplatin resistance . Collateral sensitivity . Apoptosis Introduction Antitumor activity and safety profile of platinum-based drugs have been well explored in numerous clinical and research studies. The prototype metallodrug cisplatin is a key compo- nent of various chemotherapy regimens for treatment of advanced solid tumors (e.g. testicular teratoma, ovarian carci- noma, bladder carcinoma, among others). However, it has been ascribed a set of major limitations in terms of intrinsic or acquired resistance and pronounced off-target toxicity [1]. Renal damage, ototoxicity and severe emetogenicity are prominent dose-limiting side effects of cisplatin-based chemo- therapy that often contribute to treatment failure [ 2]. Moreover, resistance to platinating agents can arise at any step of their mechanistic pathway due to cellular adaptation to stressful stimuli [3]. Therefore, recent studies are suggesting a more detailed classification of resistance related response mechanisms in respect of their sequence of emergence. Reduced cellular uptake via the copper transporter CTR1, active xenobiotic efflux and increased drug inactivation by cellular detoxifying enzyme systems are exemplary mecha- nisms of pre-target resistance. Target modifications that hin- der drug interactions with DNA are plausible mechanisms of the on-target resistance. Finally, a plethora of miscellaneous mechanisms that interfere with recruitment of DNA lesion * Georgi Momekov gmomekov@gmail.com 1 Department of Pharmacology, Pharmacotherapy and Toxicology, Faculty of Pharmacy, Medical University of Sofia, 2 Dunav Street, 1000 Sofia, Bulgaria 2 Laboratory of Biocoordination and Bioanalytical Chemistry, Faculty of Chemistry and Pharmacy, BSt. Kliment Ohridski^ Sofia University, 1, J. Bourchier Blvd., 1164 Sofia, Bulgaria 3 Department of Pharmaceutical Technology and Biopharmaceutics, Faculty of Pharmacy, Medical University of Sofia, 2 Dunav Street, 1000 Sofia, Bulgaria Investigational New Drugs https://doi.org/10.1007/s10637-019-00738-y