Over the last few years, aldo-keto reductase family 1 member C3 (AKR1C3) has been associated with the emergence of multidrug resistance (MDR), thereby hindering chemotherapy against cancer. In particular, impaired efficacy of the gold standards of induction therapy in acute myeloid leukaemia (AML) has been correlated with AKR1C3 expression, as this enzyme metabolises several drugs including anthracyclines. Therefore, the development of selective AKR1C3 inhibitors may help to overcome chemoresistance in clinical practice. In this regard, we demonstrated that Bruton’s tyrosine kinase (BTK) inhibitors ibrutinib and acalabrutinib efficiently prevented daunorubicin (Dau) inactivation mediated by AKR1C3 in both its recombinant form as well as during its overexpression in cancer cells. This revealed a synergistic effect of BTK inhibitors on Dau cytotoxicity in cancer cells expressing AKR1C3 both exogenously and endogenously, thus reverting anthracycline resistance in vitro. These findings suggest that BTK inhibitors have a novel off-target action, which can be exploited against leukaemia through combination regimens with standard chemotherapeutics like anthracyclines.

Zanubrutinib (ZAN) is a Bruton’s tyrosine kinase inhibitor recently approved for the treatment of some non-Hodgkin lymphomas. In clinical trials, ZAN is often combined with standard anthracycline (ANT) chemotherapy. Although ANTs are generally effective, drug resistance is a crucial obstacle that leads to treatment discontinuation. This study showed that ZAN counteracts ANT resistance by targeting aldo-keto reductase 1C3 (AKR1C3) and ATP-binding cassette (ABC) transporters. AKR1C3 catalyses the transformation of ANTs to less potent hydroxy-metabolites, whereas transporters decrease the ANT-effective concentrations by pumping them out of the cancer cells. In our experiments, ZAN inhibited the AKR1C3-mediated inactivation of daunorubicin (DAUN) at both the recombinant and cellular levels. In the drug combination experiments, ZAN synergistically sensitised AKR1C3-expressing HCT116 and A549 cells to DAUN treatment. Gene induction studies further confirmed that ZAN did not increase the intracellular level of AKR1C3 mRNA; thus, the drug combination effect is not abolished by enzyme induction. Finally, in accumulation assays, ZAN was found to interfere with the DAUN efflux mediated by the ABCB1, ABCG2, and ABCC1 transporters, which might further contribute to the reversal of ANT resistance. In summary, our data provide the rationale for ZAN inclusion in ANT-based therapy and suggest its potential for the treatment of tumours expressing AKR1C3 and/or the above-mentioned ABC transporters.

The article investigates Renaissance naturalists’ views on the links between plants and places where they grow. It looks at the Renaissance culture of botanical excursions and observation of plants in their natural environment and analyses the methods Renaissance naturalists used to describe relations between plants and their habitat, the influence of location on plants’ substantial and accidental characteristics, and in defining species. I worked mostly with printed sixteenth-century botanical sources and paid special attention to the work of Italian naturalist Giambattista Della Porta (1535–1615), whose thoughts on the relationship between plants and places are original, yet little known.

During the sixteenth and seventeenth centuries, plants were the object of a primarily descriptive approach: naturalists were concerned mainly with collecting and classifying. When confronted with the splendour of great herbals and florilegia, one can easily overlook the works which deal with plants from a more theoretical or philosophical perspective. This paper examines a chapter on vegetal magnetism in Athanasius Kircher’s treatise Magnes sive de arte magnetica. My analysis shows how Kircher uses the analogy with magnets to describe the various features of plants. He uses analogy as an epistemological tool. In Kircher’s view, analogy is not merely an illustration, it also helps him to show how plants with all their more-or-less peculiar morphological and physiological properties can be included in the whole order of creation.

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