Oleandrin sensitizes human osteosarcoma cells to cisplatin by preventing degradation of the copper transporter 1

Abstract

A major problem in osteosarcoma treatment is cisplatin resistance. We have reported the anti‐osteosarcoma effect of oleandrin; however, whether oleandrin sensitizes osteosarcoma to cisplatin is unknown. We investigated the chemosensitization of oleandrin and potential mechanisms in osteosarcoma cells U‐2OS, SaOS‐2, and MG‐63. The median‐effect analysis demonstrated that cisplatin + oleandrin exerted synergistic (U‐2OS and MG‐63) or additive effects (SaOS‐2), which were consistent with the changes of the intracellular accumulation of platinum (Pt) and Pt‐DNA adducts. Immunohistochemistry staining showed that the expression level of the mature form CTR1, the major influx transporter of cisplatin, was low in osteosarcoma tissue. However, oleandrin with or without cisplatin significantly increased the expression and membrane localization of the mature CTR1. Furthermore, CTR1 knockdown reversed the synergistic effect and decreased cisplatin uptake. The mRNA microarray analysis suggested that oleandrin downregulated the expression of proteasome‐related genes, which was verified by the proteasome activity assay. Besides, the proteasome inhibitor MG132 upregulated the expression of the mature CTR1 in U‐2OS and MG‐63 cells. Overall, we conclude that oleandrin sensitizes osteosarcoma cells to cisplatin in synergistic or additive manners. The synergy results from the enhanced cisplatin uptake via oleandrin‐mediated inhibition of proteasome activity and subsequent blockage of the mature CTR1 degradation

Cytotoxicity of Oleandrin Is Mediated by Calcium Influx and by Increased Manganese Uptake in Saccharomyces cerevisiae Cells

“…Apart from being a cardiac glycoside, oleandrin has been gathering attention due to its anti-tumoral [ 12 , 13 , 14 , 15 , 16 ] and antiviral potential [ 8 , 17 , 18 , 19 ], but its pharmacological use is held back by its variable toxicity. In this study, using the model S. cerevisiae , we detected oleandrin-induced fluctuations in cell Ca 2+ , which could be related to the Ca 2+ entry via the Cch1/Mid1 plasma membrane channel ( Figure 5 ).…”

“…Oleandrin is mainly responsible for the toxicity of oleander sap and, just as with digitoxin, it is thought to act as a cardiotonic by inhibiting the sodium and potassium ATPases (Na + /K + -ATPase) and subsequently increasing Ca 2+ concentration, resulting in activation of various cell survival and death pathways [10,11]. In spite of its toxicity, oleandrin has been increasingly investigated as several studies indicated its potential as an anticancer [12][13][14][15][16] as well as antiviral drug [8,[17][18][19]. The therapeutic potential of oleandrin is hampered by its cytotoxicity and by the fact that although several signaling cascades targeted by oleandrin through inhibition of Na + /K + -ATPase have been identified [20], and that it is considered that oleandrin may cause destruction cascades targeted by oleandrin through inhibition of Na + /K + -ATPase have been identified [20], and that it is considered that oleandrin may cause destruction of tumor cells by inducing oxidative stress through generation or reactive oxygen species (ROS) [21], many aspects which mediate oleandrin toxicity still remain obscure.…”

“…As oleandrin was shown to sensitize human osteosarcoma cells to cisplatin by preventing degradation of the copper transporter CTR1 [15], we also studied the cytotoxicity of oleandrin against S. cerevisiae mutants with defects in the transport of essential metal ions across the plasma membrane. In S. cerevisiae, there is an intricate system of transporters involved in the high-or low-affinity transport of essential metals, with both high and low specificity [43], e.g., Ctr1 (Cu + transporter [44]), Fet3/Ftr1 (complex involved in the transport of Fe 3+ and Cu 2+ , [45]), Fet4 (low-affinity transporter for Fe 2+/3+ and other transition metal ions [46]), Pho84 (phosphate transporter and a low-affinity divalent metal transporter [47]), Smf1 (divalent metal ion transporter with broad specificity and with high affinity for Mn 2+ [48,49]), Zrt1 (high-affinity Zn 2+ transporter [50]) and Zrt2 (low-affinity Zn 2+ transprter [51]).…”

Oleandrin Induces Immunogenic Cell Death Via the PERK/elF2α/ATF4/CHOP Pathway in Breast Cancer

“…Recent studies have revealed that oleandrin has antitumor activities in various tumors such as ovarian cancer, glioma, colon cancer, osteosarcoma, bladder cancer, breast cancer and leukemia. The working mechanism involves the suppression of Akt phosphorylation and the inhibition of mTOR (32)(33)(34)(35)(36). The botanical drug candidates of oleandrin, Anvirzel™ and PBI-05204, have been tested in phase I clinical trials for the treatment of solid tumors.…”

The functional roles of the circRNA/Wnt axis in cancer

“…CircMYO10 facilitates histone H4K16 acetylation by regulating the miR-370-3p/RUVBL1 axis and activating Wnt/β-catenin signaling in OS. Cisplatin (DDP) is a conventional chemotherapy drug in the treatment of OS [290][291][292][293]. Cisplatin resistance is a major challenge for OS chemotherapy application [294,295].…”