Natural product toosendanin reverses the resistance of human breast cancer cells to adriamycin as a novel PI3K inhibitor

Wang, Kai; Shan, Yating; Ma, Lin; Yang, Kailin; Bai, Hua; Wu, Yin; Yin, Fan; Cao, Yan

doi:10.1016/j.bcp.2018.03.022

Cited by 49 publications

(26 citation statements)

References 42 publications

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“…For instance, inhibition of PI3Kα by alpelisib was shown to attenuate the resistance against trastuzumab and taxanes in HER-2 positive breast cancer [48]. Apart from that, PI3K was shown as target to sensitize breast cancer cells for adriamycin toxicity [49] and the combined PI3K/mTOR inhibitor BEZ235, that we also used here, was shown to sensitize genetically modified CDDP resistant breast cancer cells for cytotoxicity in a recent study [50]. In our study, BEZ235 displayed significant effects to antagonize the COL1 induced sensitivity loss against MX and CDDP in MCF-7 cells, but not in MDA-MB-231.…”

Section: Discussionmentioning

confidence: 99%

Mechanisms of Matrix-Induced Chemoresistance of Breast Cancer Cells—Deciphering Novel Potential Targets for a Cell Sensitization

Jakubzig

Baltes

Henze

et al. 2018

Cancers

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Tumor cell binding to microenvironment components such as collagen type 1 (COL1) attenuates the sensitivity to cytotoxic drugs like cisplatin (CDDP) or mitoxantrone (MX), referred to as cell adhesion mediated drug resistance (CAM-DR). CAM-DR is considered as the onset for resistance mutations, but underlying mechanisms remain elusive. To evaluate CAM-DR as target for sensitization strategies, we analyzed signaling pathways in human estrogen-positive MCF-7 and triple-negative MDA-MB-231 breast cancer cells by western blot, proteome profiler array and TOP-flash assay in presence of COL1. β1-Integrins, known to bind COL1, appear as key for mediating COL1-related resistance in both cell lines that primarily follows FAK/PI3K/AKT pathway in MCF-7, and MAPK pathway in MDA-MB-231 cells. Notably, pCREB is highly elevated in both cell lines. Consequently, blocking these pathways sensitizes the cells evidently to CDDP and MX treatment. Wnt signaling is not relevant in this context. A β1-integrin knockdown of MCF-7 cells (MCF-7-β1-kd) reveals a signaling shift from FAK/PI3K/AKT to MAPK pathway, thus CREB emerges as a promising primary target for sensitization in MDA-MB-231, and secondary target in MCF-7 cells. Concluding, we provide evidence for importance of CAM-DR in breast cancer cells and identify intracellular signaling pathways as targets to sensitize cells for cytotoxicity treatment regimes.

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Section: Discussionmentioning

confidence: 99%

Mechanisms of Matrix-Induced Chemoresistance of Breast Cancer Cells—Deciphering Novel Potential Targets for a Cell Sensitization

Jakubzig

Baltes

Henze

et al. 2018

Cancers

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“…Recently, intensive studies combining molecules from traditional Chinese medicine with chemotherapeutic drugs have validated the effectiveness of this strategy in overcoming limitations faced by chemotherapeutic agents and in improving the efficacy of the chemotherapy (Huang et al, 2018; Wang et al, 2018b). Glycyrrhizin, for example, has been shown to prevent oxidative stress by restoring antioxidant enzyme levels to protect malformation and renal toxicity caused by cisplatin in mice (Arjumand and Sultana, 2011).…”

Section: Introductionmentioning

confidence: 99%

Tetramethylpyrazine Enhances the Antitumor Effect of Paclitaxel by Inhibiting Angiogenesis and Inducing Apoptosis

Zou

Liu

et al. 2019

Front. Pharmacol.

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Recent published findings have demonstrated the effectiveness of combining molecules from traditional Chinese medicine with chemotherapeutic drugs to treat cancer. Combined administration of these agents can overcome drug-mitigating responses as well as reduce adverse side effects, thereby enhancing the efficacy of the therapy. Tetramethylpyrazine (TMP), an alkaloid monomer from the medicinal herb Ligusticum chuanxiong hort, is known to exert a variety of antitumor effects including inhibition of tumor cell proliferation, metastasis, and drug resistance. In this research, we investigated antitumor effects of TMP combined with paclitaxel (PTX), a frontline chemotherapeutic drug, in vitro and in vivo . Our results indicate that TMP enhances the antitumor effects of PTX in ovarian cancer A2780 and SKOV3 cells. Furthermore, we found that combined treatment of TMP and PTX suppressed angiogenesis by inhibiting both ERK1/2 and Akt pathways and promoted apoptosis of tumor cells compared to TMP or PTX treatment alone. Moreover, TMP augmented the antitumor effects of PTX in ovarian cancer A2780 xenograft mouse models by significantly decreasing tumor burden and partially decreasing the toxicity of PTX, as evidenced by the decreased expression of proliferation and angiogenesis markers as well as the hematoxylin and eosin (H&E) staining and biochemical indexes assay. Overall, our findings provide novel mechanistic insight into the efficacy of combining of potent molecules present in traditional Chinese medicine with chemotherapeutic drugs for therapeutic intervention in cancer.

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“…With regard to whether the P-gp gene expression level was influenced by natural triterpenoids, previous studies showed controversial results. Toosendanin down-regulated ABCB1 mRNA expression level under 48 h treatment in resistant breast cancer cell MCF-7/ADM [18], whereas sipholane A 72 h treatment exhibited no influence on P-gp expression level in drug-resistant human colon cancer cell line SW620/Ad300 [19]. Besides, acerinol also demonstrated no impact on the ABCB1 mRNA level in both HepG2/ADM and MCF-7/ADR multi-drug resistant cancer cells [20].…”

Section: Discussionmentioning

confidence: 93%

Zhankuic Acids A, B and C from Taiwanofungus camphoratus Act as Cytotoxicity Enhancers by Regulating P-Glycoprotein in Multi-Drug Resistant Cancer Cells

Teng

Wang

et al. 2019

Biomolecules

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Since P-glycoprotein (P-gp)-related multidrug resistance (MDR) remains the most important unsolved problem in cancer treatment, scientists are attempting to find potential structures from natural resources. The aim of the present study was to elucidate whether the triterpenoids from Taiwanofungus camphoratus could reverse cancer MDR by influencing P-gp efflux pump. Substrates efflux assay and P-gp ATPase activity assay were conducted to reveal the molecular mechanisms of P-gp inhibition, while SRB assay, cell cycle analyses and apoptosis analyses were performed to confirm the cancer MDR modulating effects. The results indicated that Zhankuic acids A, B and C (ZA-A, ZA-B and ZA-C) impacted P-gp efflux function in competitive, noncompetitive and competitive manners, respectively. Furthermore, these triterpenoids all demonstrated inhibitory patterns on both basal P-gp ATPase activity and verapamil-stimulated ATPase activity. In terms of MDR reversal effects, ZA-A sensitized the P-gp over-expressing cell line (ABCB1/Flp-In TM -293) and MDR cancer cell line (KB/VIN) toward clinically used chemotherapeutic drugs, including doxorubicin, paclitaxel and vincristine, exhibiting the best cytotoxicity enhancing ability among investigated triterpenoids. The present study demonstrated that ZA-A, ZA-B and ZA-C, popular triterpenoids from T. camphoratus, effectively modulated the drug efflux transporter P-gp and reversed the cancer MDR issue.

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Natural product toosendanin reverses the resistance of human breast cancer cells to adriamycin as a novel PI3K inhibitor

Cited by 49 publications

References 42 publications

Mechanisms of Matrix-Induced Chemoresistance of Breast Cancer Cells—Deciphering Novel Potential Targets for a Cell Sensitization

Mechanisms of Matrix-Induced Chemoresistance of Breast Cancer Cells—Deciphering Novel Potential Targets for a Cell Sensitization

Tetramethylpyrazine Enhances the Antitumor Effect of Paclitaxel by Inhibiting Angiogenesis and Inducing Apoptosis

Zhankuic Acids A, B and C from Taiwanofungus camphoratus Act as Cytotoxicity Enhancers by Regulating P-Glycoprotein in Multi-Drug Resistant Cancer Cells

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