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.
Highlights
Sanguinarine is a natural benzophenanthridine alkaloid isolated from Sanguinaria canadensis (Papaveraceae)
Human HEK293-ABCB5 embryonic kidney cells transfected with another ATP-binding cassette (ABC)-transporter, ABCB5, were propagated in DMEM medium supplemented with 10% fetal bovine serum (FBS) and 1% penicillin/streptomycin (Invitrogen) (Kawanobe et al, 2012)
Breast cancer cells transduced with control vector (MDA-MB-231-pcDNA3) or with a cDNA for the breast cancer resistance protein BCRP (MDA-MB-231BCRP clone 23), human wild-type HCT116 (p53+/+) colon cancer cells as well as knockout clones HCT116 (p53−/−) derived by homologous recombination, non-transduced human U87MG glioblastoma multiforme cells and U87MG cells transduced with an expression vector harboring an epidermal growth factor receptor (EGFR) gene with a genomic deletion of exons 2 through 7
Summary
Sanguinarine is a natural benzophenanthridine alkaloid isolated from Sanguinaria canadensis (Papaveraceae). Sanguinarine induced apoptosis and triggered cell death signaling cascades in numerous cancer cell lines (Lee et al, 2008, 2016; Xu et al, 2012). Several modes of action have been proposed to explain the anticancer activity of sanguinarine, such as activation of the caspase machinery in mitochondria, irreversible microtubule depolymerization, depletion of nuclear topoisomerase II preventing DNA strand break reconnection, inhibition of B-DNA to Z-DNA transition altering DNA supercoiling, capping telomeres inducing rapid apoptosis, depletion of cellular glutathione, and cell cycle arrest (Rich, 1994; Das et al, 1999; Messori et al, 2001; Debiton et al, 2003; Adhami et al, 2004; Bai et al, 2006, 2008; Lopus and Panda, 2006; Nitiss, 2009). It has been shown that sanguinarine inhibits the sodium–potassium ATPase affecting the membrane permeability (Ding et al, 2002)
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