Top

Published in:

25-05-2022 | Alkaloids | Original Paper

Bioactivity inspired C₁₉-diterpenoid alkaloids for overcoming multidrug-resistant cancer

Authors: Koji Wada, Masuo Goto, Emika Ohkoshi, Kuo-Hsiung Lee, Hiroshi Yamashita

Published in: Journal of Natural Medicines | Issue 4/2022

Abstract

The pharmacological activities of C₁₉-diterpenoid alkaloids are related to their basic skeletons (e.g., aconitine-type or lycoctonine-type). Also, few studies have been reported on the chemosensitizing effects of diterpenoid alkaloids. Consequently, this study was aimed at determining the chemosensitizing effects of synthetic derivatives of lycoctonine-type C₁₉-diterpenoid alkaloids on a P-glycoprotein (P-gp)-overexpressing multidrug-resistant (MDR) cancer cell line KB-VIN. The acyl-derivatives of delpheline and delcosine showed moderate cytotoxicity against chemosensitive cancer cell lines. Among non-cytotoxic synthetic analogs (1−14), several derivatives effectively and significantly sensitized MDR cells by interfering with the drug transport function of P-gp to three anticancer drugs, vincristine, paclitaxel, and doxorubicin. The chemosensitizing effect of derivatives 2, 4, and 6 on KB-VIN cells against vincristine were more potent than 5 μM verapamil, and derivatives 4 and 13 were more effective than 5 μM verapamil for paclitaxel. Among them, 2 in particular increased the sensitivity of KB-VIN cells to vincristine by 253-fold.

Wang FP, Chen QH, Liu XY (2010) Diterpenoid alkaloids. Nat Prod Rep 27:529–570CrossRef

Amiya T, Bando H (1988) Aconitum alkaloids. In: Brossi A (ed) The Alkaloids, vol 34. Academic Press, San Diego, pp 95–179

Benn MH, Jacyno JM (1983) The toxicology and pharmacology of diterpenoid alkaloids. In: Pelletier SW (ed) Alkaloids: Chemical and Biological Perspectives, Vol. 1; Wiley-Interscience: New York, pp 153–210

Baumann M, Krause M (2004) Targeting the epidermal growth factor receptor in radiotherapy: radiobiological mechanisms, preclinical and clinical results. Radiother Oncol 72:257–266CrossRef

Diedelot C, Mirjolet JF, Barberi-Heyob M (2002) Radiation could induce p53-independent and cell cycle-unrelated apoptosis in 5-fluorouracil radiosensitized head and neck carcinoma cells. Can J Physiol Pharmacol 80:638–643CrossRef

Haveman J, Castro-Kreder N, Rodermond HM, van Bree C, Franken NA, Stalpers LJ, Zdzienicka MZ, Peters GJ (2004) Cellular response of X-ray sensitive hamster mutant cell lines to gemcitabine, cisplatin and 5-fluorouracil. Oncol Rep 12:187–192PubMed

Kvols LK (2005) Radiation sensitizers: a selective review of molecules targeting DNA and non-DNA targets. J Nucl Med 46:187S-190SPubMed

Meng LH, Zhang JS, Ding J (2001) Salvicine, a novel DNA topoisomerase II inhibitor, exerting its effects by trapping enzyme-DNA cleavage complexes. Biochem Pharmacol 62:733–741CrossRef

Pauwels B, Korst AEC, Andriessen V, Baay MFD, Pattyn GGO, Lambrechts HAJ, de Pooter CMJ, Lardon F, Vermorken JB (2005) Unraveling the mechanism of radiosensitization by gemcitabine: the role of TP53. Radiat Res 164:642–650CrossRef

10.

Qing C, Jiang C, Zhang JS, Ding J (2001) Induction of apoptosis in human leukemia K-562 and gastric carcinoma SGC-7901 cells by salvicine, a novel anticancer compound. Anticancer Drugs 12:51–56CrossRef

11.

Sonnemann J, Gekeler V, Ahibrecht K, Brischwein K, Liu C, Bader P, Muller C, Niethammer D, Beck JF (2004) Down-regulation of protein kinase Cη by antisense oligonucleotides sensitises A549 lung cancer cells to vincristine and paclitaxel. Cancer Lett 209:177CrossRef

12.

Zhang M, Boyer M, Rivory L, Hong A, Clarke S, Stevens G, Fife K (2004) Radiosensensitization of vinorelbine and gemcitabine in NCL-H460 non-small-cell lung cancer cell. Int J Radiat Oncol Biol Phys 58:353–360CrossRef

13.

Chen S, Meng L, El-Demerdash FM, Zhou L, Rizvi SAH, Cui L, Kang W (2020) Review of compounds and pharmacological effects of Delphinium. J Chem. https://doi.org/10.1155/2020/9375619CrossRef

14.

Hao DC, Xiao PG, Gu XJ (2015) Chemical and biological studies of Aconitum pharmaceutical resources. In: Hao DC, Gu XJ, Xiao PG (eds) Medicinal Plants -Chemistry, Biology and Omics-. Elsevier Amsterdam, pp 253–292

15.

Liang XX, Gao YY, Luan SX (2018) Two decades of advances in diterpenoid alkaloids with cytotoxicity activities. RSC Adv 8:23937–23946CrossRef

16.

Ren MY, Yu QT, Shi CY, Luo JB (2017) Anticancer activities of C_18-, C_19–, C_20-, and bis-diterpenoid alkaloids derived from genus aconitum. Molecules 22:267CrossRef

17.

Shen Y, Liang WJ, Shi YN, Kennelly EJ, Zhao DK (2020) Structual diversity, bioactivities, and biosynthesis of natural diterpenoid alkaloids. Nat Prod Rep 37:763–796CrossRef

18.

Wada K, Yamashita H (2019) Cytotoxic effects of diterpenoid alkaloids against human cancer cells. Molecules 24:2317CrossRef

19.

Wada K, Hazawa M, Takahashi K, Mori T, Kawahara N, Kashiwakura I (2007) Inhibitory effects of diterpenoid alkaloids on the growth of A172 human malignant cells. J Nat Prod 70:1854–1858CrossRef

20.

Hazawa M, Wada K, Takahashi K, Mori T, Kawahara N, Kashiwakura I (2009) Suppressive effects of novel derivatives prepared from Aconitum alkaloids on tumor growth. Invest New Drugs 27:111–119CrossRef

21.

Wada K, Hazawa M, Takahashi K, Mori T, Kawahara N, Kashiwakura I (2011) Structure-activity relationships and the cytotoxic effects of novel diterpenoid alkaloid derivatives against A549 human lung carcinoma cells. J Nat Med 65:43–49CrossRef

22.

Wada K, Ohkoshi E, Bastow KF, Morris-Natschke SL, Lee KH (2012) Cytotoxic esterified diterpenoid alkaloid derivatives with increased selectivity against a drug-resistant cancer cell line. Bioorg Med Chem Lett 22:249–252CrossRef

23.

Wada K, Ohkoshi E, Zhao Yu, Goto M, Morris-Natschke SL, Lee KH (2015) Evaluation of Aconitum diterpenoid alkaloids as antiproliferative agents. Bioorg Med Chem Lett 25:1525–1531CrossRef

24.

Wada K, Goto M, Shimizu T, Kusanagi N, Li KP, Lee KH, Yamashita H (2019) Structure-activity relationships and evaluation of esterified diterpenoid alkaloid derivatives as antiproliferative agents. J Nat Med 73:789–799CrossRef

25.

Calcabrini A, Meschini S, Stringaro A, Cianfriglia M, Aracia G, Molinari A (2000) Detection of P-glycoprotein in the nuclear envelope of multidrug resistant cells. Histochem J 32:599–606CrossRef

26.

Dennison JB, Jones DR, Renbarger JL, Hall SD (2007) Effect of CYP3A5 expression on vincristine metabolism with human liver microsomes. J Pharmacol Exp Ther 321:553–563CrossRef

27.

Bando H, Wada K, Tanaka J, Kimura S, Hasegawa E, Amiya T (1989) Two new diterpenoid alkaloids from Delphinium Pacific Giant and revised ¹³C-NMR assignment of delpheline. Heterocycles 29:1293–1300CrossRef

28.

Wada K, Yamamoto T, Bando H, Kawahara N (1992) Four diterpenoid alkaloids from Delphinium elatum. Phytochemistry 31:2135–2138CrossRef

29.

Wada K, Bando H, Amiya T (1985) Two new C₂₀-diterpenoid alkaloids from Aconitum yesoense var. macroyesoense (NAKAI) TAMURA. Structures of dehydrolucidusculine and N-deethyldehydrolucidusculine. Heterocycles 23:2473–2477CrossRef

30.

Nakagawa-Goto K, Oda A, Hamel E, Ohkoshi E, Lee KH, Goto M (2015) Development of a novel class of tubulin inhibitor from desmosdumotin B with a hydroxylated bicyclic B-ring. J Med Chem 58:2378–2389CrossRef

Title: Bioactivity inspired C19-diterpenoid alkaloids for overcoming multidrug-resistant cancer
Authors: Koji Wada
Masuo Goto
Emika Ohkoshi
Kuo-Hsiung Lee
Hiroshi Yamashita
Publication date: 25-05-2022
Publisher: Springer Nature Singapore
Keywords: Alkaloids
Alkaloids
Verapamil
Published in: Journal of Natural Medicines / Issue 4/2022
Print ISSN: 1340-3443
Electronic ISSN: 1861-0293
DOI: https://doi.org/10.1007/s11418-022-01629-y

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Bioactivity inspired C₁₉-diterpenoid alkaloids for overcoming multidrug-resistant cancer

Abstract

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 4/2022

Refined-JinQi-JiangTang tablet ameliorates hypertension through activation of FGF21/FGFR1 axis in fructose-fed rats

Pentacyclic triterpenes from the leaves extract of Sandoricum koetjape

Searching for constituents from plants in geographically characterized areas, Egypt, Madagascar, and Okinawa

Regulatory science of natural products

The ability of callus tissues induced from three Allium plants to accumulate health-beneficial natural products, S-alk(en)ylcysteine sulfoxides

Comprehensive profiling of phytochemicals in the fruits of Gardenia jasminoides Ellis and its variety using liquid chromatography coupled with electrospray ionization quadrupole time-of-flight mass spectrometry