Voacamine Modulates the Sensitivity to Doxorubicin of Resistant Osteosarcoma and Melanoma Cells and Does Not Induce Toxicity in Normal Fibroblasts

Condello, Maria; Cosentino, Dario; Corinti, Silvia; Felice, Gabriella Di; Multari, Giuseppina; Gallo, Francesca Romana; Arancia, Giuseppe; Meschini, Stefania

doi:10.1021/np400950h

Cited by 27 publications

(14 citation statements)

References 24 publications

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“…In addition, voacamine is an anti-trypanosomatid agent against Indian strains of Leshmania donovani, as well as Brazilian strains of Leshmania amazonensis and Trypanosoma cruzi [30]. This alkaloid was reported as not toxic in normal fibroblasts [31]. The hydroethanolic extract of Voacanga africana and voacamine isolated from this extract exert neuroprotective activity in vitro [32].…”

Section: Atommentioning

confidence: 99%

Antimycobacterial Activity of Alkaloids and Extracts from Tabernaemontana alba and T. arborea

et al. 2020

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Tuberculosis is the main cause of death from a single infectious agent. Globally, according to the World Health Organization, in 2018, there were an estimated 1.2 million tuberculosis deaths. Moreover, there is a continuous appearance of drug-resistant strains. Thus, development of new antituberculosis medicines should receive high priority. Plant-derived natural products are promising candidates for this purpose. We therefore screened alkaloid extracts obtained from the root and stem barks of the Mexican Apocynaceae species Tabernaemontana alba and Tabernaemontana arborea, as well as the pure alkaloids ibogaine, voacangine, and voacamine, tested for activity against Mycobacterium tuberculosis H37Rv and cytotoxicity to mammalian Vero cells using the resazurin microtiter and the MTT assays, respectively. The extracts were analyzed by GC-MS and HPLC-UV. T. arborea root bark alkaloid extract showed the highest activity against M. tuberculosis (MIC100 = 7.8 µg/mL) of the four extracts tested. HPLC suggested that voacangine and voacamine were the major components. The latter was isolated by column chromatography, and its chemical structure was elucidated by 1H and 13C NMR, and MS. Unambiguous assignation was performed by HSQC, HMBC, and NOESY experiments. Voacamine is a dimeric bis-indole-type alkaloid and is 15 times more potent than the monomeric ibogan-type alkaloids ibogaine and voacangine (MIC100 = 15.6, 250.0, and 250.0 µg/mL, respectively). However, all of these compounds showed cytotoxicity to Vero cells, with a poor selectivity index of 1.00, 0.16, and 1.42, respectively. This is the first report of voacamine activity against M. tuberculosis.

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Section: Atommentioning

confidence: 99%

Antimycobacterial Activity of Alkaloids and Extracts from Tabernaemontana alba and T. arborea

et al. 2020

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“…The presence of Pgp in osteosarcoma patients is a negative prognostic factor and is predictive of poor response to treatment (5)(6)(7)(8). Both natural (9,10) and synthetic (11,12) inhibitors of Pgp have been tested to reverse Dox resistance in osteosarcoma cell lines in vitro. The specific silencing of Pgp (13) or the inhibition of pathways involved in drug resistance-such as the hypoxia inducible factor-1a- (14) or polo-like kinase 1-dependent signaling (15)appears to be promising strategies, but the translation of these approaches to clinical settings is still under investigation.…”

Section: Introductionmentioning

confidence: 99%

Mitochondria-Targeted Doxorubicin: A New Therapeutic Strategy against Doxorubicin-Resistant Osteosarcoma

Buondonno

Gazzano

Jean

et al. 2016

Molecular Cancer Therapeutics

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Doxorubicin is one of the leading drugs for osteosarcoma standard chemotherapy. A total of 40% to 45% of high-grade osteosarcoma patients are unresponsive, or only partially responsive, to doxorubicin (Dox), due to the overexpression of the drug efflux transporter ABCB1/P-glycoprotein (Pgp). The aim of this work is to improve Dox-based regimens in resistant osteosarcomas. We used a chemically modified mitochondria-targeted Dox (mtDox) against Pgp-overexpressing osteosarcomas with increased resistance to Dox. Unlike Dox, mtDox accumulated at significant levels intracellularly, exerted cytotoxic activity, and induced necrotic and immunogenic cell death in Dox-resistant/Pgp-overexpressing cells, fully reproducing the activities exerted by anthracyclines in drug-sensitive tumors. mtDox reduced tumor growth and cell proliferation, increased apoptosis, primed tumor cells for recognition by the host immune system, and was less cardiotoxic than Dox in preclinical models of drug-resistant osteosarcoma. The increase in Dox resistance was paralleled by a progressive upregulation of mitochondrial metabolism. By widely modulating the expression of mitochondria-related genes, mtDox decreased mitochondrial biogenesis, the import of proteins and metabolites within mitochondria, mitochondrial metabolism, and the synthesis of ATP. These events were paralleled by increased reactive oxygen species production, mitochondrial depolarization, and mitochondria-dependent apoptosis in resistant osteosarcoma cells, where Dox was completely ineffective. We propose mtDox as a new effective agent with a safer toxicity profile compared with Dox that may be effective for the treatment of Dox-resistant/Pgp-positive osteosarcoma patients, who strongly need alternative and innovative treatment strategies. Mol Cancer Ther; 15(11); 2640-52. ©2016 AACR.

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“…Recent studies have shown that autophagy constitutes a potential target for cancer therapy and the induction of autophagy in response to therapeutics can be viewed as having a prodeath or a prosurvival role, which contributes to the anticancer efficacy as well as drug resistance (Sui et al, 2013). Voacamine, a bisindolic alkaloid isolated from the plant Peschiera fuchsiaefolia , was proved to exert a chemosensitizing effect on MDR osteosarcoma cells by inhibition of MDR1 and induction of autophagic cell death (Condello et al, 2014). Our previous study found that dioscin, another nature active component, strengthened the efficiency of ADR in MCF‐7 and MCF‐7/ADR cells through autophagy induction as well as down‐regulation of MDR1 (Wang et al, 2016).…”

Section: Discussionmentioning

confidence: 99%

Puerarin sensitized K562/ADR cells by inhibiting NF‐κB pathway and inducing autophagy

Liu

Wang

Meng

et al. 2020

Phytotherapy Research

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Puerarin is an isoflavone isolated from Pueraria lobata (Willd.) Ohwi. In the present study, reversal effect and underlying mechanisms of puerarin on multidrug resistance (MDR) were investigated in K562/ADR cells. K562/ADR cells exhibited adriamycin (ADR) resistance and higher levels of MDR1 expression compared with K562 cells. Puerarin enhanced the chemosensitivity of K562/ADR cells and increased the ADR accumulation in K562/ADR cells. The expression levels of MDR1 were downregulated by puerarin in K562/ADR cells. Luciferase reporter assay further demonstrated the inhibitory effect of puerarin on TNF-α-induced NF-κB activation. The phosphorylation of IκB-α was significantly suppressed by puerarin. In silico docking analyses suggested that puerarin well matched with the active sites of IκB-α. Moreover, a large number of autophagosomes were found in the cytoplasm of K562/ADR cells after puerarin treatment. The significant increase in LC3-II and beclin-1 was also observed, indicating autophagy induction by puerarin in K562/ADR cells. Puerarin induced cell cycle arrest and apoptosis in K562/ADR cells. Finally, puerarin inhibited phosphorylation of Akt and JNK. In conclusion, puerarin-sensitized K562/ADR cells by downregulating MDR1 expression via inhibition of NF-κB pathway and autophagy induction via Akt inhibition.

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Voacamine Modulates the Sensitivity to Doxorubicin of Resistant Osteosarcoma and Melanoma Cells and Does Not Induce Toxicity in Normal Fibroblasts

Cited by 27 publications

References 24 publications

Antimycobacterial Activity of Alkaloids and Extracts from Tabernaemontana alba and T. arborea

Antimycobacterial Activity of Alkaloids and Extracts from Tabernaemontana alba and T. arborea

Mitochondria-Targeted Doxorubicin: A New Therapeutic Strategy against Doxorubicin-Resistant Osteosarcoma

Puerarin sensitized K562/ADR cells by inhibiting NF‐κB pathway and inducing autophagy

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