REVIEW Saponins as chemosensitizing substances that improve effectiveness and selectivity of anticancer drug—Minireview of in vitro studies Paulina Koczurkiewicz 1† | Katarzyna Klaś 1† | Karolina Grabowska 2 | Kamil Piska 1 | Katarzyna Rogowska 1 | Katarzyna Wójcik‐Pszczoła 1 | Irma Podolak 2 | Agnieszka Galanty 2 | Marta Michalik 3 | Elżbieta Pękala 1 1 Department of Pharmaceutical Biochemistry, Faculty of Pharmacy Medical College, Jagiellonian University, Kraków, Poland 2 Department of Pharmacognosy, Faculty of Pharmacy Medical College, Jagiellonian University, Kraków, Poland 3 Department of Cell Biology, Faculty of Biophysics, Biochemistry and Biotechnology, Jagiellonian University, Kraków, Poland Correspondence Paulina Koczurkiewicz, Department of Pharmaceutical Biochemistry, Faculty of Pharmacy Medical College, Jagiellonian University, Medyczna 9, 30‐688 Kraków, Poland. Email: paulina.koczurkiewicz@uj.edu.pl Triterpene saponins (saponosides) are found in higher plants and display a wide range of biological and pharmacological activities. The antitumor effects of saponins have been proved by their cytotoxic, cytostatic, proapoptotic, and anti‐invasive effects in many cellular models. Saponins hold great potential for being developed into chemo- preventive and chemotherapeutic drugs. A promising way of reducing the adverse effects of chemotherapy without attenuating its efficiency is provided by the combined application of chemotherapeutic agents and saponosides in subtoxic concentrations. Until recently, saponosides were primarily used as adjuvants that enhance the effect of vaccines. In cancer therapy, saponins are applied in combina- tion with immunotoxins because they increase the selectivity of given immunotoxins against cancer cells and therefore inure normal cells to the cytotoxic effects of immunotoxins. Significantly, certain saponins have been identified that drastically enhance the efficacy of many chemotherapeutic agents, including cisplatin, paclitaxel, doxorubicin, docetaxel, mitoxantrone, and cyclophosphamide. Moreover, saponins used in combination therapy enhance the sensitivity of chemoresistant tumor cells to clinically used chemotherapeutic agents. This review sheds light on the molecular mechanisms underlying cancer co–treatment with saponins and chemotherapy, with a particular focus on modulation of the cell signaling pathways associated with the promotion and progression of cancer cell proliferation, apoptosis, and metastasis. KEYWORDS chemotherapeutics, combined therapy, triterpene saponins 1 | INTRODUCTION Saponins are natural glycosidic compounds that exert many biological activities and are distributed among a wide variety of plants. The two major groups of saponins differ in terms of the nature of aglycone moiety, which can be triterpene or steroidal. Whereas steroidal saponins are distributed mainly in monocots, triterpene saponins are characteristic of dicots and can be found in a considerable number of families (Desai, Desai, & Kaur, 2009; Güçlü‐Ustündağ & Mazza, 2007; Sparg, Light, & van Staden, 2004). One of the most promising biological Abbreviations: ARE, antioxidant response element; GPx, glutathione peroxidase; HCC, hepatocellular carcinoma; ICR, Institute of Cancer Research; MDA, malondialdehyde; Nrf2, nuclear factor (erythroid‐derived 2)‐like 2; SOD, superoxide dismutase; TBARS, thiobarbituric acid reactive substances † Paulina Koczurkiewicz and Katarzyna Klaś contributed equally to this paper. Received: 28 June 2018 Revised: 25 March 2019 Accepted: 28 March 2019 DOI: 10.1002/ptr.6371 Phytotherapy Research. 2019;1–11. © 2019 John Wiley & Sons, Ltd. wileyonlinelibrary.com/journal/ptr 1