Anticancer Activities of the Quinone-Methide Triterpenes Maytenin and 22-β-hydroxymaytenin Obtained from Cultivated Maytenus ilicifolia Roots Associated with Down-Regulation of miRNA-27a and miR-20a/miR-17-5p

Abstract

Natural triterpenes exhibit a wide range of biological activities. Since this group of secondary metabolites is structurally diverse, effects may vary due to distinct biochemical interactions within biological systems. In this work, we investigated the anticancer-related activities of the quinone-methide triterpene maytenin and its derivative compound 22-β-hydroxymaytenin, obtained from Maytenus ilicifolia roots cultivated in vitro. Their antiproliferative and pro-apoptotic activities were evaluated in monolayer and three-dimensional cultures of immortalized cell lines. Additionally, we investigated the toxicity of maytenin in SCID mice harboring tumors derived from a squamous cell carcinoma cell line. Both isolated molecules presented pronounced pro-apoptotic activities in four cell lines derived from head and neck squamous cell carcinomas, including a metastasis-derived cell line. The molecules also induced reactive oxygen species (ROS) and down-regulated microRNA-27a and microRNA-20a/miR-17-5p, corroborating with the literature data for triterpenoids. Intraperitoneal administration of maytenin to tumor-bearing mice did not lead to pronounced histopathological changes in kidney tissue, suggesting low nephrotoxicity. The wide-ranging activity of maytenin and 22-β-hydroxymaytenin in head and neck cancer cells indicates that these molecules should be further explored in plant biochemistry and biotechnology for therapeutic applications.

In Vitro Production and Exudation of 20-Hydroxymaytenin from Gymnosporia heterophylla (Eckl. and Zeyh.) Loes. Cell Culture

“…As introduced earlier, plant tissue culture techniques, such as callus and cell suspension cultures, have been commonly used to overcome a problem in a low production of the plant secondary metabolites from medicinal plants, and it has been shown to be realistic for Celastraece plants like M. ilicifolia and C. cognatum [ 14 , 24 ]. We optimized a cultivation medium by combining various concentrations of two phytohormones, such as indole-3-butyric acid (IBA) and naphthalene acetic acid (NAA), which provided a high percentage success rate in a callus formation from leaves of G. heterophylla .…”

“…Moreover, it was indicated that maytenin could effectively and specifically target cancer cells. However, maytenin demonstrated an inferior effect compared to cisplatin (the standard treatment), but it also showed less toxicity [ 14 ]. Lastly, Hernandes and his team also suggested that maytenin might prevent cancer cells from resisting cisplatin treatment by downregulating microRNAs such as miR-21-5p [ 14 ].…”

Participation of MicroRNAs in the Treatment of Cancer with Phytochemicals

“…Recently, it was noticed that the treatment of head and neck cancer cells with either maytenin or 22-β-hydroxymaytenin shows cytotoxic effects, together with a profound decrease in miR-17 and miR-20a levels. Additionally, maytenin limits metastasis of cancer in vivo, with minimal toxicity to the kidneys [ 78 ]. Moreover, oridonin diminishes the expression of miR-17 and miR-20a and triggers cell death in both doxorubicin-sensitive and -resistant leukemia cells via derepressing BCL2L11, a target mRNA of miR-17 and miR-20a [ 80 ] ( Figure 3 and Table 3 ).…”

“…In the case of maytenin, it also reduces the levels of miR-27a-3p [ 78 ] ( Figure 3 and Table 3 ). However, this miRNA was recently identified to inhibit EMT via negatively regulating Yes1-associated transcriptional regulator (YAP1) in head and neck cancer cells [ 211 ].…”

Employing optical microscopy technique to determine the tissue action of Hamamelis virginianaL. (Hamamelidaceae), Maytenus ilicifoliaMart. ex Reissek (Celastraceae) and Casearia sylvestris Sw. (Salicaceae) tinctures on skin-fixed histological sections of Wistar rats

“…As for the chemical constituents isolated from the extracts of different Celastraceae species, it has been observed that they are rich in steroidal, flavonoids, and triterpenoid substances 12 . The therapeutic properties of the plants of Celastraceae family includes antioxidant, insecticidal, cytotoxic, anticancer, antimicrobial, antinociceptive, tissue repair, and antiulcers [12][13][14][15] .…”