Synergistic Cytotoxic and Anti-invasive Effects of Mitoxantrone and Triterpene Saponins from Lysimachia ciliata on Human Prostate Cancer Cells

Abstract

Triterpene saponins are secondary metabolites typical for higher plants. They possess a wide range of pharmaceutical and biological activities. These include anti-inflammatory, vasoprotective, expectorant, and antitumor properties. In particular, the ability of saponins to enhance the cytotoxicity of chemotherapeutic drugs has opened new perspectives for their application in combined cancer chemotherapy. In this study, the biological activity of the saponin fraction isolated from (denoted as CIL-1/2) was evaluated to assess its chemosensitizing activity in prostate cancer cell lines (DU-145, PC-3). No cytotoxic or cytostatic effect of the CIL-1/2 fraction administered at the concentration of 0.5 µg/mL was observed. In contrast, cocktails of CIL-1/2 and mitoxantrone (a drug commonly used in prostate cancer therapy) exerted synergistic cytostatic and proapoptotic effects. Furthermore, the synergy of proapoptotic activities of the analyzed cocktails is accompanied by their synergistic effects on prostate cancer cell movement and invasiveness. The significantly weaker impact of this cocktail on normal prostate cells additionally adds to the significance of our data and confirms that the CIL-1/2 fraction might be considered a potent adjuvant for prostate cancer chemotherapy.

Enhanced asthma-related fibroblast to myofibroblast transition is the result of profibrotic TGF-β/Smad2/3 pathway intensification and antifibrotic TGF-β/Smad1/5/(8)9 pathway impairment

“…S1 B) 56 , because the TGF-βRII level is the same in NA and AS HBFs 36 , 56 . Dysregulation of the Smad2/3 pathway through blocking of TGF-β receptors (pharmacologically and using specific antibodies) was used to decrease the FMT potential and fibrosis, but this treatment may disturb the balance of normal processes in other cells of the organism 37 , 49 , 57 . Therefore, substances that act downstream in the TGF-β/Smad2/3 pathway, such as inhibitors of Smad2/3 phosphorylation or nuclear translocation inhibitors (SIS3, statins, fenofibrate, etc.…”

Saponins as chemosensitizing substances that improve effectiveness and selectivity of anticancer drug—Minireview of in vitro studies

“…The effects of selected saponins in co-treatment with commonly used chemotherapeutics on cancer cells; for details, see Table 1 [Colour figure can be viewed at wileyonlinelibrary.com] mitoxantrone and a saponin fraction from Lysimachia ciliata (Myrsinaceae, also known as CIL-1/2) produced significant synergistic cytostatic effects that led to apoptosis in a population of prostate cancer cells (DU-145, PC-3; Figure 1). Moreover, a synergistic anti-invasive effect of CIL-1/2 with mitoxantrone was observed in both types of prostate cancer cells of differing levels of invasiveness (Koczurkiewicz et al, 2016). Advantages of combined therapy have also been seen in prostate cancer cells treated with cocktails of mitoxantrone and a triterpene saponin, Lclet…”

“…Combination of mitoxantrone and a saponin fraction from Lysimachia ciliata (Myrsinaceae, also known as CIL‐1/2) produced significant synergistic cytostatic effects that led to apoptosis in a population of prostate cancer cells (DU‐145, PC‐3; Figure ). Moreover, a synergistic anti‐invasive effect of CIL‐1/2 with mitoxantrone was observed in both types of prostate cancer cells of differing levels of invasiveness (Koczurkiewicz et al, ). Advantages of combined therapy have also been seen in prostate cancer cells (DU‐145) treated with cocktails of mitoxantrone and a triterpene saponin, Lclet 4 (3‐ O ‐β‐ d ‐glucopyranosyl‐(1→2)‐(α‐ l ‐rhamnopyranosyl‐(1→2)‐β‐ d ‐glucopyranosyl‐(1→4)‐)‐α‐ l ‐arabinopyranosyl‐protoprimulagenin A), isolated from Lysimachia clethroides .…”

“…Many researchers have proven unfavorable activities of saponins: genotoxicity (Liu, Yu, et al, 2011), cardiotoxicity (Liang et al, 2016), and a risk of organ accumulation (Yu, Zhang, et al, 2012) or drug-drug interactions caused by the influence on CYP activity (Huang, Zheng, Zhu, Xu, & Xu, 2014). However, some studies have demonstrated a promising safety profile of saponins (Koczurkiewicz et al, 2016;Mohamed, Mammoud, & Hayen, 2009). Therefore, saponins as compounds demonstrate a wide variety of toxicological properties and should be subjected to standard drug safety examinations, with particular emphasis on their hemolytic…”

In Search of High-Yielding and Single-Compound-Yielding Plants: New Sources of Pharmaceutically Important Saponins from the Primulaceae Family

“…However, ethnomedicinal applications of P. sieboldii to treat cough and bronchitis are not widely known [14]. Besides the well-known activities of saponins such as expectorant or vasoprotectant, an increasing number of researchers are interested in the evaluation of their promising positive interactions with, for example, chemotherapeutics [15][16][17]. Their usage in pharmacy, cosmetology and the food industry as natural and efficient emulsifiers or foaming agents is also desirable [18][19][20].…”