Abstract
Recently, we have isolated and identified several bioactive flavonoids and stilbenoids with potential anticancer activity from Thai orchids. In this study, we further investigated the cytotoxic and chemosensitizing activities of these phytochemicals (namely, pinocembrin, cardamonin, isalpinin, galangin, pinosylvin monomethyl ether, 2,3′-dihydroxy-5′-methoxystilbene, (E)-2,5′-dihydroxy-2′-(4-hydroxybenzyl)-3′-methoxystilbene, 2,3-dihydroxy-3′,5′-dimethoxystilbene, 2,3′-dihydroxy-5,5′-dimethoxystilbene, 3,4′-dihydroxy-5-methoxystilbene and batatasin III) against breast cancer MCF7 cells and its two multidrug resistant (MDR) sublines (MCF7/DOX and MCF7/MX). Cytotoxicity was determined with MTT assay for the estimation of the half maximal cytotoxic concentrations (IC50). Effects of the test compounds on activities of efflux transporters (BCRP, P-gp, MRP1, and MRP2) were evaluated with substrate accumulation assays using fluorometry and flow cytometry analysis. Out of these 11 test compounds, the stilbene pinosylvin monomethyl ether displayed its cytotoxicity specifically toward MCF7 cells (IC50 = 6.2 ± 1.2 μM, 72-h incubation) with 4.96 folds higher than normal fibroblast. Its potency decreased in MCF7/DOX and MCF7/MX cells by 3.94 and 7.38 folds, respectively. Our transporter assay indicated that this stilbene significantly reduced the activities of P-gp, MRP1, and MRP2, but not BCRP. After 48-h co-incubation, this stilbene (at 2 μM) synergistically increased doxorubicin- and mitoxantrone-mediated cytotoxicity in MCF7, MCF7/DOX, and MCF7/MX cells potentially by increasing the intracellular level of cytotoxic drug. Pinosylvin monomethyl ether could sensitize breast cancer cells to chemotherapy and overcome MDR, in part, via the inhibition of drug efflux transporters.
Similar content being viewed by others
Data availability
All data generated or analyzed during this study are included in this published article.
References
Aires V, Colin DJ, Doreau A et al (2019) P-glycoprotein 1 affects chemoactivities of resveratrol against human colorectal cancer cells. Nutrients 11:2098. https://doi.org/10.3390/nu11092098
Bukowski K, Kciuk M, Kontek R (2020) Mechanisms of multidrug resistance in cancer chemotherapy. Int J Mol Sci 21:3233. https://doi.org/10.3390/ijms21093233
Chaisit T, Siripong P, Jianmongkol S (2017) Rhinacanthin-C enhances doxorubicin cytotoxicity via inhibiting the functions of P-glycoprotein and MRP2 in breast cancer cells. Eur J Pharmacol 795:50–57. https://doi.org/10.1016/j.ejphar.2016.12.002
Chou TC (2010) Drug combination studies and their synergy quantification using the Chou-Talalay method. Cancer Res 70:440–446. https://doi.org/10.1158/0008-5472.CAN-09-1947
Costea T, Vlad OC, Miclea LC et al (2020) Alleviation of multidrug resistance by flavonoid and non-flavonoid compounds in breast, lung, colorectal and prostate cancer. Int J Mol Sci 21:401. https://doi.org/10.3390/ijms21020401
Feyzizadeh M, Barfar A, Nouri Z et al (2022) Overcoming multidrug resistance through targeting ABC transporters: lessons for drug discovery. Expert Opin Drug Discov 22:1–15. https://doi.org/10.1080/17460441.2022.2112666
Indrayanto G, Putra GS, Suhud F (2021) Validation of in-vitro bioassay methods: application in herbal drug research. Profiles Drug Subst Excip Relat Methodol 46:273–307. https://doi.org/10.1016/bs.podrm.2020.07.005
Kitagawa S, Nabekura T, Takahashi T et al (2005) Structure-activity relationships of the inhibitory effects of flavonoids on P-glycoprotein-mediated transport in KB-C2 cells. Biol Pharm Bull 28:2274–2278. https://doi.org/10.1248/bpb.28.2274
Kokubo S, Ohnuma S, Murakami M et al (2021) A phenylfurocoumarin derivative reverses ABCG2-mediated multidrug resistance in vitro and in vivo. Int J Mol Sci 22:12502. https://doi.org/10.3390/ijms222212502
Lertnitikul N, Jittham P, Khankhampoch L et al (2016) Cytotoxic stilbenes from the roots of Paphiopedilum godefroyae. J Asian Nat Prod Res 18:1143–1150. https://doi.org/10.1080/10286020.2016.1183
Lertnitikul N, Pattamadilok C, Chansriniyom C, Suttisri R (2020) A new dihydrophenanthrene from Cymbidium finlaysonianum and structure revision of cymbinodin-A. J Asian Nat Prod Res 22:83–90. https://doi.org/10.1080/10286020.2018.1540605
Lertnitikul N, Liangsakul J, Jianmongkol S, Suttisri R (2022) Three new cytotoxic stilbene dimers from Paphiopedilum dianthum. Nat Prod Res 18:1–9. https://doi.org/10.1080/14786419.2022.2101049
Li H, Krstin S, Wang S, Wink M (2018a) Capsaicin and piperine can overcome multidrug resistance in cancer cells to doxorubicin. Molecules 23:557. https://doi.org/10.3390/molecules23030557
Li J, Duan B, Guo Y et al (2018b) Baicalein sensitizes hepatocellular carcinoma cells to 5-FU and Epirubicin by activating apoptosis and ameliorating P-glycoprotein activity. Biomed Pharmacother 98:806–812. https://doi.org/10.1016/j.biopha.2018.01.002
Li S, Zhao Q, Wang B et al (2018c) Quercetin reversed MDR in breast cancer cells through down-regulating P-gp expression and eliminating cancer stem cells mediated by YB-1 nuclear translocation. Phytother Res 32:1530–1536. https://doi.org/10.1002/ptr.6081
Li Y, Guo Y, Feng Z et al (2019) Involvement of the PI3K/Akt/Nrf2 signaling pathway in resveratrol-mediated reversal of drug resistance in HL-60/ADR cells. Nutr Cancer 71:1007–1018. https://doi.org/10.1080/01635581.2019.1578387
Mirzaei SA, Reiisi S, Tabari PG et al (2018) Broad blocking of MDR efflux pumps by acetylshikonin and acetoxyisovalerylshikonin to generate hypersensitive phenotype of malignant carcinoma cells. Sci Rep 8:3446. https://doi.org/10.1038/s41598-018-21710-5
Saraswathy M, Gong S (2013) Different strategies to overcome multidrug resistance in cancer. Biotechnol Adv 31:1397–1407. https://doi.org/10.1016/j.biotechadv.2013.06.004
Śliwiński T, Kowalczyk T, Sitarek P, Kolanowska M (2022) Orchidaceae-derived anticancer agents: a review. Cancers 14:754. https://doi.org/10.3390/cancers14030754
Valdameri G, Rangel LP, Spatafora C et al (2011) Methoxy stilbenes as potent, specific, untransported, and noncytotoxic inhibitors of breast cancer resistance protein. ACS Chem Biol 7:322–330. https://doi.org/10.1021/cb200435y
Waks AG, Winer EP (2019) Breast cancer treatment: a review. JAMA 321:288–300. https://doi.org/10.1001/jama.2018.19323
Wang X, Zhang H, Chen X (2019) Drug resistance and combating drug resistance in cancer. Cancer Drug Resist 2:141–160. https://doi.org/10.20517/cdr.2019.10
Wissel G, Deng F, Kudryavtsev P et al (2017) A structure-activity relationship study of ABCC2 inhibitors. Eur J Pharm Sci 103:60–69. https://doi.org/10.1016/j.ejps.2017.02.005
Wongsakul A, Lertnitikul N, Suttisri R, Jianmongkol S (2022) N-trans-p-coumaroyltyramine enhances indomethacin-and diclofenac-induced apoptosis through endoplasmic reticulum stress-dependent mechanism in MCF-7 cells. Anticancer Res 42:1833–1844. https://doi.org/10.21873/anticanres.15659
Funding
This work was supported by a grant (Fundamental Fund No. CUFRB65 hea(53)-062–33-06) from Thailand Science Research and Innovation (TSRI), Thailand. We also received graduate scholarship from Chulalongkorn University for ASEAN and Non-ASEAN countries to KL Sein.
Author information
Authors and Affiliations
Contributions
Khin Lay Sein and Suree Jianmongkol conceived and designed research. Khin Lay Sein conducted experiments. Khin Lay Sein and Suree Jianmongkol conducted data analysis and interpretation. Nonthalert Lertnitikul and Rutt Suttisri contributed the test materials. Khin Lay Sein wrote the original draft of manuscript. Rutt Suttisri and Suree Jianmongkol reviewed and edited the final draft of manuscript. All authors read and approved the manuscript.
Corresponding author
Ethics declarations
Ethical approval
Not applicable.
Competing interests
The authors declare no competing interests.
Additional information
Publisher's note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
About this article
Cite this article
Sein, K.L., Lertnitikul, N., Suttisri, R. et al. Anticancer and chemosensitizing activities of stilbenoids from three orchid species. Naunyn-Schmiedeberg's Arch Pharmacol 396, 749–758 (2023). https://doi.org/10.1007/s00210-022-02352-x
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00210-022-02352-x