Ailanthone inhibits cell growth and migration of cisplatin resistant bladder cancer cells through down-regulation of Nrf2, YAP, and c-Myc expression.

Abstract

Background: Ailanthone (Aila) is a natural active compound isolated from the Ailanthus altissima,-inhibitory effect against several cancer cell lines. Advanced bladder cancer is a common disease characterized by a frequent onset of resistance to cisplatin-based therapy. The cisplatin (CDDP) resistance is accompanied by an increase in Nrf2 protein expression which contributes to conferring resistance. Recently, we demonstrated a crosstalk between Nrf2 and YAP. YAP has also been demonstrated to play an important role in chemoresistance of bladder cancer. Purpose: We analyzed the antitumor effect of Aila in sensitive and CDDP-resistant bladder cancer cells and the molecular mechanisms involved in Aila activity. Study design: Sensitive and CDDP-resistant 253J B-V and 253J bladder cancer cells, and intrinsically CDDP-resistant T24 bladder cancer cells were used. Cells were treated with diverse concentrations of Aila and proliferation, cell cycle, apoptosis and gene expressions were determined. Methods: Aila toxicity and proliferation were determined by MTT and colony forming methods, respectively. Cell cycle was determined at cytofluorimeter by PI staining method Apoptosis was detected using Annexin V and PI double staining followed by quantitative flow cytometry. Expressions of Nrf2, Yap, c-Myc, and housekeeping genes were determined by western blot with specific antibodies. Cell migration was detected by wound healing and Boyden chamber analysis. Results: Aila inhibited growth of sensitive and CDDP-resistant bladder cancer cells with the same effectiveness, and reduced cell migration with higher effectiveness in CDDP resistant cells. Interestingly, Aila strongly reduced Nrf2 expression in all cell lines. Cell cycle analysis revealed an accumulation of Aila-treated cells in G0/G1 phase. Moreover, Aila significantly reduced YAP and c-Myc protein expression. The random and the oriented migration were strongly inhibited by Aila treatment, in particular in CDDP-resistant cells. Conclusions: Aila, inhibited proliferation and invasiveness of bladder cancer cells. Its high effectiveness in CDDP resistant cells could be related to the inhibition of Nrf2 , YAP and c-Myc expressions. Aila could represent a new tool to overcome CDDP resistance in bladder cancer.

Carbosilane Dendrimers Loaded with siRNA Targeting Nrf2 as a Tool to Overcome Cisplatin Chemoresistance in Bladder Cancer Cells

“…In various types of cancers, it has been shown that the adaptive response mediated by Nrf2 contributes to the resistance towards chemotherapeutic pro-oxidant drugs, such as cisplatin (CDDP). Recently, we provided evidence on its key role in sustaining CDDP resistance in bladder cancer [ 4 , 5 , 6 ], in agreement with other reports [ 7 ]. For these reasons, Nrf2 can be a promising target to overcome chemoresistance.…”

Bidirect effects from cisplatin combine with rosmarinic acid (RA) or hot water extracts of Glechoma hederacea (HWG) on renal cancer cells

“…The combination of anti-tumor agents should be able to produce synergistic or additive therapeutic e cacies, reduced side effects and minimal drug resistance. Experimental strategies that investigate combinational therapy of CDDP with natural plant extracts/plant-derived agents to maintain the desired antitumor e cacy have been reported [9,36,37]. In this study, HWG in combined with CDDP inhibits the invasion of these RCC cells, especially at a concentration of more than 100 mg/mL and inhibited the wound-healing migration of these RCC cells, especially at a concentration of more than 200 mg/mL.…”

Bidirect effects from cisplatin combine with rosmarinic acid (RA) or hot water extracts of Glechoma hederacea (HWG) on renal cancer cells

“…The combination of anti-tumor agents should be able to produce synergistic or additive therapeutic efficacies, reduced side effects and minimal drug resistance. Experimental strategies that investigate combinational therapy of CDDP with natural plant extracts/plant-derived agents to maintain the desired antitumor efficacy have been reported [9,36,37]. In this study, HWG in combination with CDDP inhibits the invasion of these RCC cells, especially at a concentration of more than 100 µg/mL and inhibited the wound-healing migration of these RCC cells, especially at a concentration of more than 200 µg/mL.…”