Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2018 Mar 2;23(3):557.
doi: 10.3390/molecules23030557.

Capsaicin and Piperine Can Overcome Multidrug Resistance in Cancer Cells to Doxorubicin

Hanmei Li  1 , Sonja Krstin  2 , Shihui Wang  3 , Michael Wink  4
Affiliations

Capsaicin and Piperine Can Overcome Multidrug Resistance in Cancer Cells to Doxorubicin

Hanmei Li et al. Molecules. .

Abstract

Background: Multidrug resistance (MDR) can develop in cancer cells after treatment with anticancer drugs, mainly due to the overexpression of the ATP-binding cassette (ABC) transporters. We analyzed the ability of two pungent-tasting alkaloids-capsaicin and piperine from Capsicum frutescens and Piper nigrum, respectively-to reverse multidrug resistance in the cancer cell lines Caco-2 and CEM/ADR 5000, which overexpress P-glycoprotein (P-gp) and other ABC transporters.

Methods: The MTT assay was first used to determine the cytotoxicity of doxorubicin, the alkaloids, and digitonin alone, and then their combinations. Furthermore, rhodamine (Rho) 123 and calcein-AM were used to detect the effects of alkaloids on the activity of P-gp.

Results: Capsaicin and piperine synergistically enhanced the cytotoxicity of doxorubicin in Caco-2 and CEM/ADR 5000 cells. Furthermore, capsaicin and piperine increased the intracellular accumulation of the fluorescent P-glycoprotein (P-gp) substrates rhodamine and calcein and inhibited their efflux from the MDR cell lines.

Conclusion: Our study has demonstrated that capsaicin and piperine are P-gp substrates and have potential chemosensitizing activity, which might be interesting for the development of novel modulators of multidrug resistance.

Keywords: CCRF-CEM; CEM/ADR 5000; Caco-2; HCT 116; capsaicin; multidrug resistance; piperine.

PubMed Disclaimer

Conflict of interest statement

The authors declare no competing financial interest.

Figures

Figure 1
Figure 1
Chemical structures of (a) capsaicin and (b) piperine.
Figure 2
Figure 2
Isobologram analysis of the drugs’ interactions. The IC50 concentration of doxorubicin is set on the x-axis and the IC50 of the secondary metabolitesn the y-axis. The line connecting these two points means additivity. Points below the line indicate synergy. Dox—doxorubicin; Cap—capsaicin; Pip—piperine; Dig—digitonine.
Figure 2
Figure 2
Isobologram analysis of the drugs’ interactions. The IC50 concentration of doxorubicin is set on the x-axis and the IC50 of the secondary metabolitesn the y-axis. The line connecting these two points means additivity. Points below the line indicate synergy. Dox—doxorubicin; Cap—capsaicin; Pip—piperine; Dig—digitonine.
Figure 3
Figure 3
Effects of alkaloids and the positive control with verapamil on rhodamine (Rho) 123 retention in Caco-2 cells. Cells treated with DMSO were used as a solvent control. Data are presented as the mean ± SD.
Figure 4
Figure 4
Histograms of flow cytometry of calcein accumulation in CEM/ADR 5000 and CCRF-CEM cells. Cells treated with DMSO were used as the negative control. The numbers drawn in this graph mean concentrations (μM). Cells treated with 20 μM verapamil were used as the positive control.
See this image and copyright information in PMC

References

    1. Hanahan D., Weinberg R.A. The hallmarks of cancer. Cell. 2000;100:57–70. doi: 10.1016/S0092-8674(00)81683-9. - DOI - PubMed
    1. Singh S., Sharma B., Kanwar S.S., Kumar A. Lead Phytochemicals for anticancer drug development. Front. Plant Sci. 2016;7:1667. doi: 10.3389/fpls.2016.01667. - DOI - PMC - PubMed
    1. Gottesman M.M., Fojo T., Bates S.E. Multidrug resistance in cancer: Role of ATP-dependent transporters. Nat. Rev. Cancer. 2002;2:48–58. doi: 10.1038/nrc706. - DOI - PubMed
    1. Szakacs G., Paterson J.K., Ludwig J.A., Booth-Genthe C., Gottesman M.M. Targeting multidrug resistance in cancer. Nat. Rev. Drug Discov. 2006;5:219–234. doi: 10.1038/nrd1984. - DOI - PubMed
    1. Pauwels E.K., Erba P., Mariani G., Gomes C.M. Multidrug resistance in cancer: Its mechanism and its modulation. Drug News Perspect. 2007;20:371–377. doi: 10.1358/dnp.2007.20.6.1141496. - DOI - PubMed

MeSH terms