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Secalonic acid D as a selective cytotoxic substance on the cancer cells adapted to nutrient starvation

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Abstract

Cancer cells adapted to the microenvironment in tumor such as hypoxic and nutrient-starved conditions are now paid much attention as the therapeutic target of cancer. In the course of search for selective cytotoxic substances against cancer cells adapted to nutrient starvation, xanthone derivative of secalonic acid D (1) was isolated from culture extract of marine-derived Penicillium oxalicum. Compound 1 showed cytotoxic activity on the human pancreatic carcinoma PANC-1 cells adapted to glucose-starved conditions with IC50 value of 0.6 µM, whereas IC50 value of compound 1 against PANC-1 cells under general culture conditions was calculated to be more than 1000 µM. Further study indicated that compound 1 inhibited the Akt signaling pathway under glucose-starved conditions, and slightly affected the induction of glucose-regulated protein 78 (GRP78), and these effects would be mediated by the uncoupling action of compound 1 on the mitochondria.

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References

  1. Vaupel P, Kallinowski F, Okunieff P (1989) Blood flow, oxygen and nutrient supply, and metabolic microenvironment of human tumors: a review. Cancer Res 49:6449–6465

    PubMed  CAS  Google Scholar 

  2. Rohwer N, Cramer T (2011) Hypoxia-mediated drug resistance: novel insights on the functional interaction of HIFs and cell death pathways. Drug Resist Updat 14:191–201

    Article  CAS  Google Scholar 

  3. Chen S, Rehman SK, Zhang W, Wen A, Yao L, Zhang J (2010) Autophagy is a therapeutic target in anticancer drug resistance. Biochim Biophys Acta 1806:220–229

    PubMed  CAS  Google Scholar 

  4. Izuishi K, Kato K, Ogura T, Kinoshita T, Esumi H (2000) Remarkable tolerance of tumor cells to nutrient deprivation: possible new biochemical target for cancer therapy. Cancer Res 60:6201–6207

    PubMed  CAS  Google Scholar 

  5. Ueda J, Athikomkulchai S, Miyatake R, Saiki I, Esumi H, Awale S (2013) (+)-Grandifloracin, an antiausterity agent, induces autophagic PANC-1 pancreatic cancer cell death. Drug Des Dev Ther 8:39–47

    Google Scholar 

  6. Ron D, Walter P (2007) Walter signal integration in the endoplasmic reticulum unfolded protein response. Nat Rev Mol Cell Biol 8:519–529

    Article  CAS  Google Scholar 

  7. Lee AS (2007) GRP78 Induction in cancer: therapeutic and prognostic implications. Cancer Res 67:3496–3499

    Article  CAS  Google Scholar 

  8. Jin S, DiPaola RS, Mathew R, White E (2007) Metabolic catastrophe as a means to cancer cell death. J Cell Sci 120:379–383

    Article  CAS  Google Scholar 

  9. Lu J, Kunimoto S, Yamazaki Y, Kaminishi M, Esumi H (2004) Kigamicin D, a novel anticancer agent based on a new anti-austerity strategy targeting cancer cells' tolerance to nutrient starvation. Cancer Sci 95:547–552

    Article  CAS  Google Scholar 

  10. Awale S, Dibwe DF, Balachandran C, Fayez S, Feineis D, Lombe BK, Bringmann G (2018) Ancistrolikokine E3, a 5,8′-coupled naphthylisoquinoline alkaloid, eliminates the tolerance of cancer cells to nutrition starvation by inhibition of the Akt/mTOR/autophagy signaling pathway. J Nat Prod 81:2282–2291

    Article  CAS  Google Scholar 

  11. Kim J, Hwang J, Cha M, Yoon M, Son E, Tomida A, Ko B, Song S, Shin-ya K, Hwang Y, Park H (2010) Arctigenin blocks the unfolded protein response and shows therapeutic antitumor activity. J Cell Physiol 224:33–40

    PubMed  CAS  Google Scholar 

  12. Arai M, Kawachi T, Kotoku N, Nakata C, Kamada H, Tsunoda S, Tsutsumi Y, Endo H, Inoue M, Sato H, Kobayashi M (2016) Furospinosulin-1, marine spongean furanosesterterpene, suppresses the growth of hypoxia-adapted cancer cells by binding to transcriptional regulators p54nrb and LEDGF/p75. ChemBioChem 17:181–189

    Article  CAS  Google Scholar 

  13. Kawachi T, Tanaka S, Fukuda A, Sumii Y, Setiawan A, Kotoku N, Kobayashi M, Arai M (2019) Target identification of the marine natural products dictyoceratin-A and -C as selective growth inhibitors in cancer cells adapted to hypoxic environments. Mar Drugs 17:E163

    Article  CAS  Google Scholar 

  14. Tang R, Kimishima A, Ishida R, Setiawan A, Arai M (2020) Selective cytotoxicity of epidithiodiketopiperazine DC1149B, produced by marine-derived Trichoderma lixii on the cancer cells adapted to glucose starvation. J Nat Med 74:153–158

    Article  CAS  Google Scholar 

  15. Arai M, Kamiya K, Shin D, Matsumoto H, Hisa T, Setiawan A, Kotoku N, Kobayashi M (2016) N-Methylniphatyne A, a new 3-alkylpyridine alkaloid as an inhibitor of the cancer cells adapted to nutrient starvation, from an Indonesian marine sponge of Xestospongia sp. Chem Pharm Bull 64:766–771

    Article  CAS  Google Scholar 

  16. Kotoku N, Ishida R, Matsumoto H, Arai M, Tida K, Setiawan A, Muraoka M, Kobayashi M (2017) Biakamides A-D, unique polyketides from a marine sponge, act as selective growth inhibitors of tumor cells adapted to nutrient starvation. J Org Chem 82:1705–1718

    Article  CAS  Google Scholar 

  17. Steyn PS (1970) The isolation, structure and absolute configuration of secalonic acid D, the toxic metabolite of Penicillium oxalicum. Tetrahedron 26:51–57

    Article  CAS  Google Scholar 

  18. Chen G, Jiang Z, Bai J, Wang H, Zhang S, Pei Y (2015) Isolation, structure determination, in vivo/vitro assay and docking study of a xanthone with antitumor activity from fungus Penicillium oxalicum. Rec Nat Prod 9:184–189

    Google Scholar 

  19. Momose I, Ohba S, Tatsuda D, Kawada M, Masuda T, Tsujiuchi G, Yamori T, Esumi H, Ikeda D (2010) Mitochondrial inhibitors show preferential cytotoxicity to human pancreatic cancer PANC-1 cells under glucose-deprived conditions. Biochem Biophys Res Commun 392:460–466

    Article  CAS  Google Scholar 

  20. Kawai K, Nakamaru T, Maebayashi Y, Nozawa Y, Yamazaki M (1983) Inhibition by secalonic acid D of oxidative phosphorylation and Ca2+-induced swelling in mitochondria isolated from rat livers. Appl Environ Microbiol 46:793–796

    Article  CAS  Google Scholar 

  21. Weatherly LM, Shim J, Hashmi HN, Kennedy RH, Hess ST, Gosse JA (2016) Antimicrobial agent triclosan is a proton ionophore uncoupler of mitochondria in living rat and human mast cells and in primary human keratinocytes. J Appl Toxicol 36:777–789

    Article  CAS  Google Scholar 

  22. Ren H, Tian L, Gu Q, Zhu W (2006) Secalonic acid D; a cytotoxic constituent from marine lichen-derived fungus Gliocladium sp. T31. Arch Pharm Res 29:59–63

    Article  CAS  Google Scholar 

  23. Guru SK, Pathania AS, Kumar S, Ramesh D, Kumar M, Rana S, Kumar A, Malik F, Sharma PR, Chandan BK, Jaglan S, Sharma JP, Shah BA, Tasduq SA, Lattoo SK, Faruk A, Saxena AK, Vishwakarma RA, Bhushan S (2015) Secalonic acid-D represses HIF1α/VEGF-mediated angiogenesis by regulating the Akt/mTOR/p70S6K signaling cascade. Cancer Res 75:2886–2896

    Article  CAS  Google Scholar 

  24. Arai M, Shin D, Kamiya K, Ishida R, Setiawan A, Kotoku N, Kobayashi M (2017) Marine spongean polybrominated diphenyl ethers, selective growth inhibitors against the cancer cells adapted to glucose starvation, inhibits mitochondrial complex II. J Nat Med 71:44–49

    Article  CAS  Google Scholar 

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Acknowledgements

The human pancreatic carcinoma cell line, PANC-1 (RCB2095), was provided by the RIKEN BRC through the National Bio-Resource Project of the MEXT, Japan. This research was funded by Platform Project for Supporting Drug Discovery and Life Science Research (Basis for Supporting Innovative Drug Discovery and Life Science Research [BINDS]) from AMED (Grant no. JP19am0101084), Kobayashi International Scholarship Foundation, and a Grant-in-Aid for Scientific Research B (Grant nos. 18H02096 and 17H04645) from JSPS to MA.

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Authors and Affiliations

  1. Graduate School of Pharmaceutical Sciences, Osaka University, Yamadaoka 1-6, Suita, Osaka, 565-0871, Japan

    Rui Tang, Atsushi Kimishima & Masayoshi Arai

  2. Department of Chemistry, Faculty of Science, Lampung University, Jl. Prof. Dr. Sumantri Brodjonegoro No. 1, Bandar Lampung, 35145, Indonesia

    Andi Setiawan

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  1. Rui Tang
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  2. Atsushi Kimishima
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  4. Masayoshi Arai
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Correspondence to Masayoshi Arai.

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Tang, R., Kimishima, A., Setiawan, A. et al. Secalonic acid D as a selective cytotoxic substance on the cancer cells adapted to nutrient starvation. J Nat Med 74, 495–500 (2020). https://doi.org/10.1007/s11418-020-01390-0

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  • DOI: https://doi.org/10.1007/s11418-020-01390-0

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