Natural Product Albiziabioside A Conjugated with Pyruvate Dehydrogenase Kinase Inhibitor Dichloroacetate To Induce Apoptosis-Ferroptosis-M2-TAMs Polarization for Combined Cancer Therapy

Wei, Gaofei; Sun, Jiahong; Luan, Weijing; Hou, Zhuang; Wang, Shuai; Cui, Shanshan; Cheng, Maosheng; Liu, Yang

doi:10.1021/acs.jmedchem.9b00644

Cited by 37 publications

(42 citation statements)

References 43 publications

(64 reference statements)

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“…The generated hydroxyl radicals subsequently induce lethal ferroptosis to tumor cells ( 54 ). A novel conjugate AlbA-DCA was developed via inhibition of the GPX4 pathway and elimination of procarcinogenic M2-TAMs to suppress tumor progression in breast cancer ( 53 ) ( Table 2 and Figure 3 ). Another study reported that M1 phagocytes exert higher ferroptosis resistance than M2 phagocytes, but that inducible nitric oxide synthase (iNOS)/NO-enrichment of phagocytes can modulate the sensibility of phagocytes to ferroptosis.…”

Section: Ferroptosis In Tumor Microenvironments and Immunotherapy Of mentioning

confidence: 99%

Ferroptosis in Cancer Treatment: Another Way to Rome

Luo

et al. 2020

Front. Oncol.

118

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Ferroptosis is a newly described type of programmed cell death and intensively related to both maintaining homeostasis and the development of diseases, especially cancers. Inducing ferroptosis leads to mitochondrial dysfunction and toxic lipid peroxidation in cells, which plays a pivotal role in suppressing cancer growth and progression. Here, we reviewed the existing studies about the molecular mechanisms of ferroptosis involved in different antitumor treatments, such as chemotherapy, targeted therapy, radiotherapy, and immunotherapy. We focused in particular on the distinct combinatorial therapeutic effects such as the synergistic sensitization effect and the drug-resistance reversal achieved when using ferroptosis inducers with conventional cancer therapy. Finally, we discussed the challenges and opportunities in clinical applications of ferroptosis. The application of nanotechnolgy and other novel technologies may provide a new direction in ferroptosis-driven cancer therapies.

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Section: Ferroptosis In Tumor Microenvironments and Immunotherapy Of mentioning

confidence: 99%

Ferroptosis in Cancer Treatment: Another Way to Rome

Luo

et al. 2020

Front. Oncol.

118

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“…Synthetic oleanolic saponins (Figure 2) have been evaluated on their antitumor [14,18,21,[29][30][31][32][33][34][35][36][37], anti-Alzheimer [38], antiviral [39,40], antiglucosidase [41], immunomodulating [42], and detoxification [43] activities (Table 1). Yang and co-workers reported a series of structures derivatized from potent antitumor Pulsatilla saponins, hederacolchiside A and D, elucidating the selectivity between the antitumor activity and hemolytic toxicity of compounds.…”

Section: Oleanolic Acidmentioning

confidence: 99%

“…To further improve antitumor efficacy, a secondary amine moiety of AlbA was conjugated with dichloroacetate (6), a pyruvate dehydrogenase kinase inhibitor, to disrupt glycolysis pathway in cells, leading to increased intracellular reactive oxygen species (ROS) and decreased accumulation of lactic acid in the tumor microenvironment. The cancer cell death was induced by caspase-dependent pathway activation, GPX4 pathway suppression, and lipid peroxidation accumulation, which can be summarized into apoptosis-ferroptosis-M2-TAM polarization [30]. Sun and co-workers constructed the synthesis method of four naturally occurring oleanolic saponins, revealing that monodesmosidic saponin exhibited higher antitumor cytotoxicity than bidesmosidic saponin [29].…”

Section: Oleanolic Acidmentioning

confidence: 99%

Biological and Pharmacological Effects of Synthetic Saponins

Juang

Liang

2020

Molecules

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Saponins are amphiphilic molecules consisting of carbohydrate and either triterpenoid or steroid aglycone moieties and are noted for their multiple biological activities—Fungicidal, antimicrobial, antiviral, anti-inflammatory, anticancer, antioxidant and immunomodulatory effects have all been observed. Saponins from natural sources have long been used in herbal and traditional medicines; however, the isolation of complexed saponins from nature is difficult and laborious, due to the scarce amount and structure heterogeneity. Chemical synthesis is considered a powerful tool to expand the structural diversity of saponin, leading to the discovery of promising compounds. This review focuses on recent developments in the structure optimization and biological evaluation of synthetic triterpenoid and steroid saponin derivatives. By summarizing the structure–activity relationship (SAR) results, we hope to provide the direction for future development of saponin-based bioactive compounds.

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“…It was reported that natural products generated ROS to promote cancer cell apoptosis (40)(41)(42)(43)(44), and in the current study a rescue experiment was performed to reveal the role of ROS in PPII inhibition. With a test of concentration gradient of N-acetyl-L-cysteine (NAC, a ROS scavenger), in U87 cells the PPII inhibition was reversed from 4 mg/mL NAC (Figure 5A), and in U251 cells the PPII inhibition was reversed from 8 mg/mL NAC by CCK-8 assays (Figure 5B).…”

Section: Ros Mediated Ppii Inhibition In U87 and U251 Cells Via Bax/cyt-cmentioning

confidence: 92%

Promotion of Ros-mediated Bax/Cyt-c apoptosis by polyphyllin II leads to suppress growth and aggression of glioma cells

Cheng¹,

Xue²,

Fang³

et al. 2021

Transl Cancer Res TCR

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Background: Gliomas remain among the most difficult cancers to treat, with a 5-year overall survival no greater than 5%. Many saponins showed a wide spectrum of anti-cancer activities at low concentration.Polyphyllin II is one of the common saponins from Paris polyphylla. However, the effect of Polyphyllin II on glioma cells has not been evaluated. Objective of the present study was to investigate whether Polyphyllin II have inhibition on glioma cells, and the possible mechanisms. Methods: The viability of U87 and U251 cells was detected by cell counting kit-8, cell counting real time cellular analysis and cell clone formation methods. Transwell was used to estimate the aggression of U87 and U251. The cell apoptosis rate was tested by flow cytometry. The morphological change was determined by transmission electron microscopy. The levels of AKT, phosphorylation of AKT, Bax, Bcl-2, cytochrome c, and cleaved caspase 3 proteins were assessed by Western blot. N-acetyl-L-cysteine was used to check the role of ROS in polyphyllin II inhibition to glioma cells. Results: Polyphyllin II showed significant suppress to proliferation and aggression of U87 and U251 in a dose-and time-dependent manner. Result of flow cytometry confirmed that Polyphyllin II induced apoptosis to U87 and U251 cells. Transmission electron microscopy observation revealed majority of the glioma cells treated with Polyphyllin II had turgidity of mitochondrion, disarrangement, diminution and vacuolization, those refer to mitochondrial apoptosis. Western blot indicated that Polyphyllin II promoted cyt-c, Bax, caspase 3 and cleaved-caspase 3, and decreased Bcl-2, AKT and p-AKT. Rescue experiments using N-acetyl-L-cysteine, a reactive oxygen species scavenger, reversed the levels of Bax and cyt-c, and the inhibition in Polyphyllin II-treated U87 and U251 cells. Conclusions:The present findings revealed that polyphyllin II may be a potential drug against glioma.

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Natural Product Albiziabioside A Conjugated with Pyruvate Dehydrogenase Kinase Inhibitor Dichloroacetate To Induce Apoptosis-Ferroptosis-M2-TAMs Polarization for Combined Cancer Therapy

Cited by 37 publications

References 43 publications

Ferroptosis in Cancer Treatment: Another Way to Rome

Ferroptosis in Cancer Treatment: Another Way to Rome

Biological and Pharmacological Effects of Synthetic Saponins

Promotion of Ros-mediated Bax/Cyt-c apoptosis by polyphyllin II leads to suppress growth and aggression of glioma cells

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