Molecular Determinants of Sensitivity or Resistance of Cancer Cells Toward Sanguinarine

Abstract

For decades, natural products represented a significant source of diverse and unique bioactive lead compounds in drug discovery field. In Clinical oncology, complete tumors remission is hampered by the development of drug-resistance. Therefore, development of cytotoxic agents that may overcome drug resistance is urgently needed. Here, the natural benzophenanthridine alkaloid sanguinarine has been studied for its cytotoxic activity against multidrug resistance (MDR) cancer cells. We investigated the role of the ATP-binding cassette (ABC) transporters BCRP/ABCG2, P-glycoprotein/ABCB1 and its close relative ABCB5 in drug resistance. Further drug resistance mechanisms analyzed in this study were the tumor suppressor TP53 and the epidermal growth factor receptor (EGFR). Multidrug resistant cells overexpressing BCRP, ABCB5 and mutated ΔEGFR were not cross-resistant toward sanguinarine. Interestingly, P-gp overexpressing cells were hypersensitive to sanguinarine. Doxorubicin uptake assay carried by flow cytometry revealed that sanguinarine is a potent inhibitor of the P-gp transporter. Moreover, immunoblotting analysis proved that P-gp was downregulated in a dose dependent manner after treating P-gp overexpressing cells with sanguinarine. It was surmised that The inhibition of NFκB activity might explain the collateral sensitivity in CEM/ADR5000 cells. The COMPARE and hierarchical cluster analyses of transcriptome-wide expression profiles of tumor cell lines of the National Cancer Institute identified genes involved in various cellular processes (immune response, inflammation signaling, cell migration and microtubule formation) significantly correlated with log10IC50 values for sanguinarine. In conclusion, sanguinarine may have therapeutic potential for treating multidrug resistant tumors.

Betulinic Acid Exerts Cytotoxic Activity Against Multidrug-Resistant Tumor Cells via Targeting Autocrine Motility Factor Receptor (AMFR)

“…Molecular docking was done in an approach previously reported by us (Saeed et al, 2018 ). Briefly, the PDB files of different AMFR cytosolic C terminal domains and AMF were obtained from protein data bank (registered ids are shown in Table 3 ).…”

Cytotoxicity of nimbolide towards multidrug-resistant tumor cells and hypersensitivity via cellular metabolic modulation

“…The uptake of 20 μM doxorubicin (University Hospital Pharmacy, Mainz, Germany) was measured after 24 h in the presence or absence of nimbolide and compared to verapamil 100 μM, a known P-glycoprotein inhibitor (Sigma Aldrich, Taufkirchen, Germany). An excitation wavelength of 488 nm was selected, and doxorubicin mean fluorescence intensity (MFI) was measured using a band pass filter of 530/30 nm to collect the emitted light [ 60 ]. Measurements were performed by using a BD FACSCalibur™ (Beckton Dickinson, GmbH, Heidelberg, Germany), and the results were analyzed and visualized using FlowJo software.…”

“…Afterwards, Luminata™ Classico Western HRP substrate (Merck Millipore, Schwalbach, Germany) was added and incubated for 3 min in the dark. Blot signals were detected and analyzed with Alpha Innotech FluorChem Q system (Biozym, Oldendorf, Germany) [ 60 ].…”

Ivermectin reverses the drug resistance in cancer cells through EGFR/ERK/Akt/NF-κB pathway

“…Multidrug resistance reversal agents, also known as MDR regulators/modulators or chemotherapy sensitizers, have been found to ameliorate the drug resistance in cancer cells in vitro and in animal models in vivo [5, 11, 12]. However, these agents have failed to demonstrate satisfactory efficacy in clinical trials due to the poor reversal efficacy, excessive toxicity, or interference with the pharmacokinetics of chemotherapeutic drugs [5, 12–14]. Therefore, it is urgently needed to develop novel MDR reversal agents that could be further used clinically for the treatment of the resistant cancers.…”