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Euphorbia seguieriana ssp. seguieriana Necker (ES) and Euphorbia cyparissias (EC) with a habitat in the Deliblato Sands were the subject of this examination. The latexes of these so far insufficiently investigated species of the Euphorbia genus are used in traditional medicine for the treatment of wounds and warts on the skin. To determine their chemical composition, non-targeted screening of the latexes’ chloroform extracts was performed using liquid chromatography coupled with quadrupole time-of-flight mass spectrometry employing an electrospray ionization source (LC-ESI QTOF MS). The analysis of the obtained results showed that the latexes of ES and EC represent rich sources of diterpenes, tentatively identified as jatrophanes, ingenanes, tiglianes, myrsinanes, premyrsinanes, and others. Examination of the anticancer activity of the ES and EC latex extracts showed that both extracts significantly inhibited the growth of the non-small cell lung carcinoma NCI-H460 and glioblastoma U87 cell lines as well as of their corresponding multi-drug resistant (MDR) cell lines, NCI-H460/R and U87-TxR. The obtained results also revealed that the ES and EC extracts inhibited the function of P-glycoprotein (P-gp) in MDR cancer cells, whose overexpression is one of the main mechanisms underlying MDR.

Euphorbia cyparissias L. (cypress spurge) is one of the many species of the genus Euphorbia. Like other plant species of the genus, E. cyparissias is a source of biologically active compounds [1, 2]. The aim of this research was to profile the chloroform-methanol latex extract and detect the type of secondary metabolites of Serbian E. cyparissias, collected in Deliblato Sand (Serbia) in May 2022, using liquid chromatography – electrospray ionisation mass spectrometry. Based on the obtained results, terpene derivatives have been found as the most abundant in the latex extract, mainly diterpenes (jatrophanes and ingenanes) and triterpenes. Also, the anticancer activ ity of the latex extract on the cell lines NCI-H460, NCI-H460/R, U87, U87/ TxR and MRC-5, as well as the ability to inhibit P-gp, were examined. Latex extract exhibited anticancer activity against all tested cell lines, and also proved to be a strong P-gp inhibitor. The obtained results are in accordance with the literature data because jatrophanes are well-known strong P-gp inhibitors [3]. These preliminary results indicate that this plant material is a rich source of biologically active compounds and detailed phytochemical research of E. cyparissias is further planned.

Background: Doxorubicin (DOX) has been very effective against glioblastoma invitro. Its application in vivo is hampered because it cannot pass the blood–brainbarrier (BBB). Significant research efforts are invested to overcome this limitation.Sclareol (SC) is an aromatic compound naturally found in clary sage. Thecombination of SC and DOX showed promising effects in different tumor types invitro and in vivo. Therefore, we tested their combination and innovative hybridmolecules (SC:DOX) on glioblastoma cells with the expression of P-glycoprotein, amajor component of BBB and cancer multidrug resistance marker. Methods:Cytotoxicity and selectivity towards glioblastoma cells of SC, DOX, theircombination, and SC:DOX were examined by MTT assay. The effect of SC on DOXaccumulation was determined by flow cytometry. We also studied SC:DOXaccumulation, cellular uptake, localization imaging, and DNA damage induction.Results: The effects of simultaneous SC and DOX treatments demonstrated theconsiderable potential of SC to reverse DOX resistance in glioblastoma cells andincrease DOX accumulation. SC:DOX hybrids, named CON1 and CON2 were lesscytotoxic than DOX, but with reduced resistance and increased selectivity towardsglioblastoma cells. Cellular uptake of CON1 and CON2 was increased in glioblastomacells compared to DOX. Perinuclear localization of CON1 and CON2 vs. nuclearlocalization of DOX as well as no DNA damaging effects suggest a differentmechanism of action for SC:DOX. Conclusion: The combination of SC and DOX, andtheir innovative hybrids, could be considered a promising strategy that can overcomethe limitations of DOX application in glioblastoma.

Drug resistance remains the major cause of cancer treatment failure especially at the late stage of the disease. However, based on their versatile chemistry, metal and metalloid compounds offer the possibility to design fine-tuned drugs to circumvent and even specifically target drug-resistant cancer cells. Based on the paramount importance of platinum drugs in the clinics, two main areas of drug resistance reversal strategies exist: overcoming resistance to platinum drugs as well as multidrug resistance based on ABC efflux pumps. The current review provides an overview of both aspects of drug design and discusses the open questions in the field. The areas of drug resistance covered in this article involve: 1) Altered expression of proteins involved in metal uptake, efflux or intracellular distribution, 2) Enhanced drug efflux via ABC transporters, 3) Altered metabolism in drug-resistant cancer cells, 4) Altered thiol or redox homeostasis, 5) Altered DNA damage recognition and enhanced DNA damage repair, 6) Impaired induction of apoptosis and 7) Altered interaction with the immune system. This review represents the first collection of metal (including platinum, ruthenium, iridium, gold, and copper) and metalloid drugs (e.g. arsenic and selenium) which demonstrated drug resistance reversal activity. A special focus is on compounds characterized by collateral sensitivity of ABC transporter-overexpressing cancer cells. Through this approach, we wish to draw the attention to open research questions in the field. Future investigations are warranted to obtain more insights into the mechanisms of action of the most potent compounds which target specific modalities of drug resistance.

Glioblastoma (GBM), as the most aggressive brain tumor, displays a high expression of Src tyrosine kinase, which is involved in the survival, migration, and invasiveness of tumor cells. Thus, Src emerged as a potential target for GBM therapy. The effects of Src inhibitors pyrazolo[3,4-d]pyrimidines, Si306 and its prodrug pro-Si306 were investigated in human GBM cell lines (U87 and U87-TxR) and three primary GBM cell cultures. Primary GBM cells were more resistant to Si306 and pro-Si306 according to the 3-(4,5-Dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay. However, the ability of all GBM cells to degrade the extracellular matrix was considerably compromised after Si306 and pro-Si306 applications. Besides reducing the phosphorylation of Src and its downstream signaling pathway components, both compounds decreased the phosphorylated form of focal adhesion kinase (FAK) and epidermal growth factor receptor (EGFR) expression, showing the potential to suppress the aggressiveness of GBM. In vivo, Si306 and pro-Si306 displayed an anti-invasive effect against U87 xenografts in the zebrafish embryo model. Considering that Si306 and pro-Si306 are able to cross the blood-brain barrier and suppress the spread of GBM cells, we anticipate their clinical testing in the near future. Moreover, the prodrug showed similar efficacy to the drug, implying the rationality of its use in clinical settings.