Timosaponin AIII Suppresses RAP1 Signaling Pathway to Enhance the Inhibitory Effect of Paclitaxel on Nasopharyngeal Carcinoma

Li, Xiaofeng; Lu, Wen; Zhou, Tianjiao; Zhao, Feng; Li, Yang

doi:10.1155/2022/6756676

Cited by 5 publications

(5 citation statements)

References 33 publications

(36 reference statements)

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“…Active ingredients isolated from traditional medical herbs are considered promising and potentially valuable resources for developing anticancer drugs. TIA has recently received particular attention for its potential to be developed as an anticancer agent [29] because TIA has been demonstrated to exert potent and diverse antitumor activities including interfering with invasion and migration [30][31][32][33][34], autophagy [35][36][37], reversing drug resistance [38][39][40][41], and inducing apoptosis [42][43][44][45][46][47]. However, the effect of TIA on glioblastoma tumorigeneity remains unanswered.…”

Section: Discussionmentioning

confidence: 99%

Functional Axis of PDE5/cGMP Mediates Timosaponin-AIII-Elicited Growth Suppression of Glioblastoma U87MG Cells

et al. 2023

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Glioblastoma (GBM) is the most aggressive brain tumor, with high mortality. Timosaponin AIII (TIA), a steroidal saponin isolated from the medicinal plant Anemarrhena asphodeloides Bge., has been shown to possess anticancer properties in various cancer types. However, the effect of TIA on GBM is unknown. In this study, we reveal that TIA not only inhibited U87MG in vitro cell growth but also in vivo tumor development. Moreover, we found that the cause of TIA-induced cell growth suppression was apoptosis. When seeking to uncover antitumor mechanisms of TIA, we found that TIA diminished the expression of cGMP-specific phosphodiesterase 5(PDE5) while elevating the levels of guanylate cyclases (sGCβ), cellular cGMP, and phosphorylation of VASPser239. Following the knockdown of PDE5, PDE5 inhibitor tadalafil and cGMP analog 8-Bro-cGMP both inhibited cell growth and inactivated β-catenin; we reason that TIA elicited an antitumor effect by suppressing PDE5, leading to the activation of the cGMP signaling pathway, which, in turn, impeded β-catenin expression. As β-catenin is key for cell growth and survival in GBM, this study suggests that TIA elicits its anti-tumorigenic effect by interfering with β-catenin function through the activation of a PDE5/cGMP functional axis.

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Section: Discussionmentioning

confidence: 99%

Functional Axis of PDE5/cGMP Mediates Timosaponin-AIII-Elicited Growth Suppression of Glioblastoma U87MG Cells

et al. 2023

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“…It has been reported that TSAIII strengthens the suppressive activity of paclitaxel (PTX) on the proliferation of nasopharyngeal carcinoma CNE-1 and HNE-2 cells, upregulates the expression of Bad and RAP1GAP, downregulates the expression of Bcl-2, RAP1, and RasGRP2, and promotes PTX-induced apoptosis. TSAIII can synergize with PTX to protect against tumor growth in a xenograft mouse model [ 45 ] ( Table 1 ).…”

Section: The Anticancer Effects Of Tsaiiimentioning

confidence: 99%

The Potential Role of Timosaponin-AIII in Cancer Prevention and Treatment

et al. 2023

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Cancer, as one of the leading causes of death worldwide, has challenged current chemotherapy drugs. Considering that treatments are expensive, alongside the resistance of tumor cells to anticancer drugs, the development of alternative medicines is necessary. Anemarrhena asphodeloides Bunge, a recognized and well-known medicinal plant for more than two thousand years, has demonstrated its effectiveness against cancer. Timosaponin-AIII (TSAIII), as a bioactive steroid saponin isolated from A. asphodeloides, has shown multiple pharmacological activities and has been developed as an anticancer agent. However, the molecular mechanisms of TSAIII in protecting against cancer development are still unclear. In this review article, we provide a comprehensive discussion on the anticancer effects of TSAIII, including proliferation inhibition, cell cycle arrest, apoptosis induction, autophagy mediation, migration and invasion suppression, anti-angiogenesis, anti-inflammation, and antioxidant effects. The pharmacokinetic profiles of TSAII are also discussed. TSAIII exhibits efficacy against cancer development. However, hydrophobicity and low bioavailability may limit the application of TSAIII. Effective delivery systems, particularly those with tissue/cell-targeted properties, can also significantly improve the anticancer effects of TSAIII.

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“…The microwells had flat bottoms instead of curved ones, enabling the evaluation of cell migratory behavior. PTX has been identified as a candidate for the treatment of nasopharyngeal carcinoma (NPC), but additional measures are needed to suppress its side effects and enhance its delivery efficiency [ 27 , 28 ]. For the first time, PEGylated paclitaxel nanoparticles (PEG-PTX NPs) were applied to treat NPC43 cells in microwells without and with a cover.…”

Section: Introductionmentioning

confidence: 99%

PEGylated Paclitaxel Nanomedicine Meets 3D Confinement: Cytotoxicity and Cell Behaviors

Lin

Xiao

et al. 2023

JFB

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Investigating the effect of nanomedicines on cancer cell behavior in three-dimensional (3D) platforms is beneficial for evaluating and developing novel antitumor nanomedicines in vitro. While the cytotoxicity of nanomedicines on cancer cells has been widely studied on two-dimensional flat surfaces, there is little work using 3D confinement to assess their effects. This study aims to address this gap by applying PEGylated paclitaxel nanoparticles (PEG-PTX NPs) for the first time to treat nasopharyngeal carcinoma (NPC43) cells in 3D confinement consisting of microwells with different sizes and a glass cover. The cytotoxicity of the small molecule drug paclitaxel (PTX) and PEG-PTX NPs was studied in microwells with sizes of 50 × 50, 100 × 100, and 150 × 150 μm2 both with and without a concealed top cover. The impact of microwell confinement with varying sizes and concealment on the cytotoxicity of PTX and PEG-PTX NPs was analyzed by assessing NPC43 cell viability, migration speed, and cell morphology following treatment. Overall, microwell isolation was found to suppress drug cytotoxicity, and differences were observed in the time-dependent effects of PTX and PEG-PTX NPs on NPC43 cells in isolated and concealed microenvironments. These results not only demonstrate the effect of 3D confinement on nanomedicine cytotoxicity and cell behaviors but also provide a novel method to screen anticancer drugs and evaluate cell behaviors in vitro.

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Timosaponin AIII Suppresses RAP1 Signaling Pathway to Enhance the Inhibitory Effect of Paclitaxel on Nasopharyngeal Carcinoma

Cited by 5 publications

References 33 publications

Functional Axis of PDE5/cGMP Mediates Timosaponin-AIII-Elicited Growth Suppression of Glioblastoma U87MG Cells

Functional Axis of PDE5/cGMP Mediates Timosaponin-AIII-Elicited Growth Suppression of Glioblastoma U87MG Cells

The Potential Role of Timosaponin-AIII in Cancer Prevention and Treatment

PEGylated Paclitaxel Nanomedicine Meets 3D Confinement: Cytotoxicity and Cell Behaviors

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