Dataset Information

Shotgun proteomic elucidation of Synergistic mechanisms of Cannabidiol and SN-38 in the MCF7 cells

ABSTRACT: We evaluted the synergyistic interactions of cannabidiol (CBD) with standard chemotherapeutic agents such as Docetaxel (DOC), doxorubicin (DOX), paclitaxel (PTX), vinorelbine (VIN), and 7-Ethyl-10-hydroxycamptothecin (SN38) in MCf7 cells ultising different synergy metrics. Then we explored the synergistic mechanisms on the proteome level of the most synergistic combination (CBD and SN38 in a molar ratio of 371:1, respectively)

INSTRUMENT(S): Synapt MS

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Permanent Cell Line Cell, Cell Culture

DISEASE(S): Breast Cancer

SUBMITTER: Muhammad Alsherbiny

LAB HEAD: Chun Guang Li

PROVIDER: PXD026587 | Pride | 2021-11-03

REPOSITORIES: Pride

ACCESS DATA

Dataset's files

Source:

			Action	DRS
	210506_CSN.zip	Other
	CBD_vs_Control.csv	Csv
	CSN.DerivedFromSearch062651a4-868a-4952-8365-3a8d2ebd2749.mgf	Mgf
	CSN.mzid.gz	Mzid
	M_vs_Singles__synergy_.csv	Csv

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Publications

Synergistic Interactions of Cannabidiol with Chemotherapeutic Drugs in MCF7 Cells: Mode of Interaction and Proteomics Analysis of Mechanisms.

Alsherbiny Muhammad A MA Bhuyan Deep J DJ Low Mitchell N MN Chang Dennis D Li Chun Guang CG

International journal of molecular sciences 20210918 18

Cannabidiol (CBD), a nonpsychoactive phytocannabinoid, has recently emerged as a potential cytotoxic agent in addition to its ameliorative activity in chemotherapy-associated side effects. In this work, the potential interactions of CBD with docetaxel (DOC), doxorubicin (DOX), paclitaxel (PTX), vinorelbine (VIN), and 7-ethyl-10-hydroxycamptothecin (SN-38) were explored in MCF7 breast adenocarcinoma cells using different synergy quantification models. The apoptotic profiles of MCF7 cells after th ...[more]

PMID: 34576262

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Project description:The combination of natural products with standard chemotherapeutic agents offers a promising strategy to enhance the efficacy of standard chemotherapy by reducing their dosage and side effects. The standard chemotherapeutic drug for breast and other cancer types- doxorubicin(DOX), also known as Adriamycin (an anthracycline) has several disadvantages including severe side effects and development of drug resistance. Recently, we reported the broad spectrum pharmacological activity and potential markers of Australian propolis extract (AP-1). In the present study, we explored the synergistic interactions of AP-1 with DOX against MCF-7 cells by implementing different synergy quantitation models. To identify the potential anticancer metabolites in AP-1, biochemometric and metabolomics-driven study was performed. Furthermore, we evaluated the molecular mechanisms involved by analysing the apoptotic profile (using flow cytometry and proteome array of 35 apoptotic proteins) and oxidative status (using reactive oxygen species detection) of the MCF-7 cells upon treatment with the most synergistic combination. The underlying synergistic mechanism against the MCF-7 cells was also studied using label-free quantification proteomics analysis. Five prenylated stilbenes were identified as the most discriminant metabolites in the most active AP-1 fraction, three of them previously isolated from AP-1 with IC50 values in the range 0.68-2.7 µM against the MCF-7 cells. Strong synergy was observed when AP-1 was combined with DOX in the ratio of 100:0.29 (w/w) as validated by different synergy quantitation models including combination index (CI), HSA, ZIP, LOEWE, and BLISS. AP-1 significantly enhanced the inhibitory effect of DOX (p < 0.05) against the MCF-7 cell proliferation in a dose-dependent manner with significant reduction of ROS production (p < 0.05; compared to DOX alone). AP-1 also enhanced the apoptotic effect of DOX significantly after 24 h of treatment with a shift of DOX-induced necrosis to apoptosis. Significant upregulation of catalase, HTRA2/Omi, FADD together with TRAIL-mediated apoptosis, DR5 and DR4 (p < 0.05) was observed which contributed to the anti-proliferative activity of AP-1 against the MCF-7 cells. The enhancement of pro-apoptotic p27, PON2 and catalase with reduction of anti-apoptotic XIAP, HSP60 and HIF-1α may be associated with the improved apoptosis in the MCF-7 cells observed in the Annexin V-7AAD flow cytometry analysis of the synergistic combination compared to the mono treatments. Furthermore, a significant increase of antioxidant proteins including catalase and PON2 was observed upon treatment with the synergistic combination which may be associated with the parallel enhancement of apoptosis. Shotgun proteomics in the synergistic combination-treated cells identified 21 significantly dysregulated proteins involving the TP53/ATM-regulated non-homologous end-joining pathway and double-strand breaks repairs, recruiting the overexpressed BRCA1 and curtailed RIF1 encoded proteins. The overexpression of UPF2 was noticed after the treatment with the synergistic combination which could assist to overcome doxorubicin resistance-associated long non-coding RNA and decline the metastasis of the MCF-7 cells. In summary, we propose a promising AP-1 and DOX synergistic combination against the MCF-7 cells and highlighted the possible synergistic mechanisms of action together with the key prenylated metabolites of AP-1. Further in vivo and clinical studies are warranted on this synergistic combination.

Project description:Milk, renowned for its nutritional value, harbours bioactive compounds, including lactoferrin (Lf) [1], immunoglobulins, and functional proteins suggesting broader functionalities beyond nutrition. Lf, an iron glycoprotein, exhibits antimicrobial properties against bacteria, fungi, and viruses."In"this st"dy, Immune Powder (a functional dairy formulation) and Fractionated Milk Protein (FMP; a blend of bioactive proteins isolated from skim milk) containing Lf, zinc, and immunoglobulins produced by Ausnutria Australia Dairy Pty Ltd were evaluated for their broad spectrum pharmacological activity. In particular, the study aims to investigate the antibacterial (against pathogenic Escherichia coli), prebiotic (promoting Lactobacillus delbrueckii growth), anti-inflammatory (against RAW264.7 macrophages), and antiviral (against human coronavirus 229E, HCoV-229E cultured on MCR-5 cells) effects of the formulations. In addition, the impact of simulated gastric digestion on the efficacy of the formulations was explored. LCMS-based proteomics analysis was implemented to unveil cellular and molecular mechanisms underlying antiviral activity. The Immune Powder demonstrated antibacterial activity against E. coli (up to 99.74 ± 11.47% inhibition at 62.5 mg/mL), coupled with prebiotic action (10.84 ± 2.2 viability fold change at 125 mg/mL), albeit diminished post-digestion (p <0.01). The Immune Powder effectively mitigated inflammation by reducing NO production, with efficacy declining post-digestion (p < 0.0001). The potential antiviral activity of Immune Powder against HCoV-229E also shown an increase of 2.62 ± 0.42 in cell viability when treated at 500 µg/mL. Similarly, FMP exhibited antibacterial potency pre-digestion at high concentration (95.56 ± 1.23% inhibition at 125 mg/mL), and post-digestion at lower doses (61.82 ± 5.58% inhibition at 3906.25 µg/mL). FMP also shown enhanced prebiotic activity post-digestion (p < 0.0001), anti-inflammation pre-digestion, and significant antiviral activity against HCoV-229E (1.72 ± 0.52 cell viability fold change). The proteomics study suggested both formulas shared similar antiviral mechanism by inhibiting scavenger receptor binding and ECM interaction.