Skip to content
2000
image of Polysaccharides from Sepia Esculenta Ink Promote Apoptosis via Inhibition of Autophagy in Cisplatin-exposed Triple-Negative Breast Cancer Cells

Abstract

Introduction

Sepia Ink Polysaccharide (SIP) is a well-characterized, marine-derived glycosaminoglycan with demonstrated multifunctional properties; however, its pharmacological mechanisms remain unclear. This study aims to investigate the anti-tumor mechanism of SIP1 from Sepia esculenta ink in the treatment of triple-negative breast cancer (TNBC), with a focus on apoptosis and autophagy.

Methods

MDA-MB-231 cells exposed to cisplatin (CP) and SIP1 were assessed for apoptosis and autophagy by evaluating cell morphology, apoptosis and autophagy rates, and the expression of key genes involved in these processes using double staining, flow cytometry, and Western blotting.

Results

The data revealed that SIP1 induced apoptosis in TNBC cells, as demonstrated by an increased apoptosis rate, an elevated expression level of the Caspase-3 protein, a decreased expression of Bcl-2, and an elevated Bax/Bcl-2 ratio. Additionally, SIP1 did not impact autophagy. CP induced both apoptosis and autophagy of breast cancer cells. The combination of SIP1 and CP exhibited synergistic effects, enhancing apoptosis by 2.33-fold compared to SIP1 alone and 1.25-fold compared to CP alone, while simultaneously reducing autophagy levels (0.84-fold compared to CP alone), as verified by the Beclin 1 protein content.

Discussion

This work discovered that SIP1, a sulfated glycosaminoglycan with a low content of sulfate ester groups derived from Sepia esculenta ink, induced apoptosis by inhibiting autophagy, providing a novel perspective for a deeper understanding of the anti- tumor mechanism of SIP. Currently, the underlying molecular mechanisms by which SIP1 modulates the crosstalk between apoptosis and autophagy in TNBC cells remain unknown and require further investigation.

Conclusion

This study demonstrates that SIP1 is effective in inducing apoptosis and promotes cisplatin-induced apoptosis by repressing cisplatin-induced autophagy in MDA-MB-231 cells.

© 2025 Bentham Science Publishers
Loading

Article metrics loading...

/content/journals/cmc/10.2174/0109298673379638250707061138
2025-07-30
2025-09-10

  • From This Site

    /content/journals/cmc/10.2174/0109298673379638250707061138
    dcterms_title,dcterms_subject,pub_keyword
    -contentType:Contributor -contentType:Concept -contentType:Institution
    10
    5
Loading full text...

Full text loading...

References

  1. Sung H. Ferlay J. Siegel R.L. Laversanne M. Soerjomataram I. Jemal A. Bray F. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J. Clin. 2021 71 3 209 249 10.3322/caac.21660 33538338
    [Google Scholar]
  2. Coles C.E. Earl H. Anderson B.O. Barrios C.H. Bienz M. Bliss J.M. Cameron D.A. Cardoso F. Cui W. Francis P.A. Jagsi R. Knaul F.M. McIntosh S.A. Phillips K.A. Radbruch L. Thompson M.K. André F. Abraham J.E. Bhattacharya I.S. Franzoi M.A. Drewett L. Fulton A. Kazmi F. Inbah Rajah D. Mutebi M. Ng D. Ng S. Olopade O.I. Rosa W.E. Rubasingham J. Spence D. Stobart H. Vargas Enciso V. Vaz-Luis I. Villarreal-Garza C. Arreola-Ornelas H. Bhadelia A. Boughey J.C. Chatterjee S. Dodwell D. Doubova S. Du Plooy D. Essue B. Goel N. Gralow J. Hawley S. Kiely B. Mann R. Mertz S. Palmieri C. Poortmans P. Spanic T. Stephen L. Symmans F. Towns C. Verhoeven D. Vinnicombe S. Watkins D. Yip C-H. Zikmund-Fisher B. The Lancet breast cancer commission. Lancet 2024 403 10439 1895 1950 10.1016/S0140‑6736(24)00747‑5 38636533
    [Google Scholar]
  3. Al-Bahlani S.M. Al-Bulushi K.H. Al-Alawi Z.M. Al-Abri N.Y. Al-Hadidi Z.R. Al-Rawahi S.S. Cisplatin induces apoptosis through the endoplasmic reticulum-mediated, calpain 1 pathway in triple-negative breast cancer cells. Clin. Breast Cancer 2017 17 3 e103 e112 10.1016/j.clbc.2016.12.001 28089626
    [Google Scholar]
  4. Sahin K. Tuzcu M. Basak N. Caglayan B. Kilic U. Sahin F. Kucuk O. Sensitization of cervical cancer cells to cisplatin by genistein: The role of NFκB and Akt/mTOR signaling pathways. J. Oncol. 2012 2012 1 6 10.1155/2012/461562 23056046
    [Google Scholar]
  5. Kalai Selvi S. Vinoth A. Varadharajan T. Weng C.F. Vijaya Padma V. Neferine augments therapeutic efficacy of cisplatin through ROS- mediated non-canonical autophagy in human lung adenocarcinoma (A549 cells). Food Chem. Toxicol. 2017 103 28 40 10.1016/j.fct.2017.02.020 28223119
    [Google Scholar]
  6. Alessandra Gammone M. Riccioni G. Galvano F. D’Orazio N. Novel therapeutic strategies against cancer: Marine-derived drugs may ee the answer? Anticancer. Agents Med. Chem. 2016 16 12 1549 1557 10.2174/1871520616666160211123841 26863883
    [Google Scholar]
  7. Li F. Luo P. Liu H. A potential adjuvant agent of chemotherapy: Sepia ink polysaccharides. Mar. Drugs 2018 16 4 106 10.3390/md16040106 29597272
    [Google Scholar]
  8. Chen S. Xu J. Xue C. Dong P. Sheng W. Yu G. Chai W. Sequence determination of a non-sulfated glycosaminoglycan-like polysaccharide from melanin-free ink of the squid Ommastrephes bartrami by negative-ion electrospray tandem mass spectrometry and NMR spectroscopy. Glycoconj. J. 2008 25 5 481 492 10.1007/s10719‑007‑9096‑2 18219573
    [Google Scholar]
  9. Liu C. Li X. Li Y. Feng Y. Zhou S. Wang F. Structural characterisation and antimutagenic activity of a novel polysaccharide isolated from Sepiella maindroni ink. Food Chem. 2008 110 4 807 813 10.1016/j.foodchem.2008.02.026 26047264
    [Google Scholar]
  10. Liu H.Z. Tao Y.X. Luo P. Deng C.M. Gu Y.P. Yang L. Zhong J.P. Preventive effects of a novel polysaccharide from Sepia esculenta ink on ovarian failure and its action mechanisms in cyclophosphamide-treated mice. J. Agric. Food Chem. 2016 64 28 5759 5766 10.1021/acs.jafc.6b01854 27337058
    [Google Scholar]
  11. Lin Z. Luo P. Lin X. Chen Y. Zhang Y. Li F. Tan X. Liu H. Effects of a sulfated glycosaminoglycan from Sepia esculenta ink on transcriptional and metabolic profiles of Saccharomyces cerevisiae. Carbohydr. Polym. 2022 276 118715 10.1016/j.carbpol.2021.118715 34823761
    [Google Scholar]
  12. Le X.Y. Luo P. Gu Y.P. Tao Y.X. Liu H.Z. Interventional effects of squid ink polysaccharides on cyclophosphamide-associated testicular damage in mice. Bratisl. Med. J. 2015 116 5 334 339 10.4149/BLL_2015_063 25924645
    [Google Scholar]
  13. Le X. Luo P. Gu Y. Tao Y. Liu H. Squid ink polysaccharide reduces cyclophosphamide-induced testicular damage via Nrf2/ARE activation pathway in mice. Iran. J. Basic Med. Sci. 2015 18 8 827 831 26557973
    [Google Scholar]
  14. Zuo T. Cao L. Li X. Zhang Q. Xue C. Tang Q. The squid ink polysaccharides protect tight junctions and adherens junctions from chemotherapeutic injury in the small intestinal epithelium of mice. Nutr. Cancer 2015 67 2 364 371 10.1080/01635581.2015.989369 25587665
    [Google Scholar]
  15. Gu Y.P. Yang X.M. Duan Z.H. Luo P. Shang J.H. Xiao W. Tao Y.X. Zhang D.Y. Zhang Y.B. Liu H.Z. Inhibition of chemotherapy-induced apoptosis of testicular cells by squid ink polysaccharide. Exp. Ther. Med. 2017 14 6 5889 5895 10.3892/etm.2017.5342 29285137
    [Google Scholar]
  16. Gu Y.P. Yang X.M. Duan Z.H. Shang J.H. Luo P. Xiao W. Zhang D.Y. Liu H.Z. Squid ink polysaccharide prevents autophagy and oxidative stress affected by cyclophosphamide in Leydig cells of mice: A pilot study. Iran. J. Basic Med. Sci. 2017 20 11 1194 1199 10.22038/IJBMS.2017.9491 29299195
    [Google Scholar]
  17. Gu Y.P. Yang X.M. Luo P. Li Y.Q. Tao Y.X. Duan Z.H. Xiao W. Zhang D.Y. Liu H.Z. Inhibition of acrolein-induced autophagy and apoptosis by a glycosaminoglycan from Sepia esculenta ink in mouse Leydig cells. Carbohydr. Polym. 2017 163 270 279 10.1016/j.carbpol.2017.01.081 28267506
    [Google Scholar]
  18. Luo P. Liu H.Z. Le X.Y. Du H. Kang X.H. Squid ink polysaccharide prevents chemotherapy induced injury in the testes of reproducing mice. Pak. J. Pharm. Sci. 2018 31 1 25 29 29348080
    [Google Scholar]
  19. Liu H. Li F. Luo P. Effect of carboxymethylation and phosphorylation on the properties of polysaccharides from Sepia esculenta ink: antioxidation and anticoagulation in vitro. Mar. Drugs 2019 17 11 626 10.3390/md17110626 31683929
    [Google Scholar]
  20. Liu H. Zhang Y. Li M. Luo P. Beneficial effect of Sepia esculenta ink polysaccharide on cyclophosphamide-induced immunosuppression and ovarian failure in mice. Int. J. Biol. Macromol. 2019 140 1098 1105 10.1016/j.ijbiomac.2019.08.200 31449864
    [Google Scholar]
  21. Li F. Lin Z. Wu Y. Luo P. Wu J. Liu H. Antioxidant, anticoagulant and thrombolytic properties of SIP-IV, a sulfated polysaccharide from Sepia esculenta ink, and its derivatives. Food Biosci. 2022 49 101959 10.1016/j.fbio.2022.101959
    [Google Scholar]
  22. Chen S. Wang J. Xue C. Li H. Sun B. Xue Y. Chai W. Sulfation of a squid ink polysaccharide and its inhibitory effect on tumor cell metastasis. Carbohydr. Polym. 2010 81 3 560 566 10.1016/j.carbpol.2010.03.009
    [Google Scholar]
  23. Zong A. Zhao T. Zhang Y. Song X. Shi Y. Cao H. Liu C. Cheng Y. Qu X. Cao J. Wang F. Anti-metastatic and anti-angiogenic activities of sulfated polysaccharide of Sepiella maindroni ink. Carbohydr. Polym. 2013 91 1 403 409 10.1016/j.carbpol.2012.08.050 23044150
    [Google Scholar]
  24. Zong A. Liu Y. Zhang Y. Song X. Shi Y. Cao H. Liu C. Cheng Y. Jiang W. Du F. Wang F. Anti-tumor activity and the mechanism of SIP-S: A sulfated polysaccharide with anti-metastatic effect. Carbohydr. Polym. 2015 129 50 54 10.1016/j.carbpol.2015.04.017 26050887
    [Google Scholar]
  25. Liu H.Z. Xiao W. Gu Y.P. Tao Y.X. Zhang D.Y. Du H. Shang J.H. Polysaccharide from Sepia esculenta ink and cisplatin inhibit synergistically proliferation and metastasis of triple-negative breast cancer MDA-MB-231 cells. Iran. J. Basic Med. Sci. 2016 19 12 1292 1298 10.22038/ijbms.2016.7913 28096961
    [Google Scholar]
  26. Jiang W. Cheng Y. Zhao N. Li L. Shi Y. Zong A. Wang F. Sulfated polysaccharide of Sepiella Maindroni ink inhibits the migration, invasion and matrix metalloproteinase-2 expression through suppressing EGFR-mediated p38/MAPK and PI3K/Akt/mTOR signaling pathways in SKOV-3 cells. Int. J. Biol. Macromol. 2018 107 Pt A 349 362 10.1016/j.ijbiomac.2017.08.178 28870748
    [Google Scholar]
  27. Jiang W. Tian W. Ijaz M. Wang F. Inhibition of EGF-induced migration and invasion by sulfated polysaccharide of Sepiella maindroni ink via the suppression of EGFR/Akt/p38 MAPK/MMP-2 signaling pathway in KB cells. Biomed. Pharmacother. 2017 95 95 102 10.1016/j.biopha.2017.08.050 28830011
    [Google Scholar]
  28. Shan L. Liu W. Zhan Y. Sulfated polysaccharide of Sepiella maindroni ink targets Akt and overcomes resistance to the FGFR inhibitor AZD4547 in bladder cancer. Aging 2019 11 18 7780 7795 10.18632/aging.102286 31545294
    [Google Scholar]
  29. Tian W. Song X. Wang F. Jiang W. Study on the preparation and biological activities of low molecular weight squid ink polysaccharide from Sepiella maindroni. Int. J. Biol. Macromol. 2023 237 124040 10.1016/j.ijbiomac.2023.124040 36933594
    [Google Scholar]
  30. Klionsky D.J. Abdelmohsen K. Abe A. Abedin M.J. Abeliovich H. Arozena A.A. Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition). Autophagy 2016 12 1 1 222 10.1080/15548627.2015.1100356 26799652
    [Google Scholar]
  31. Zhu Y. Zhang C. Yin Q. Xu W. Luo Y. Ou J. FOXO4 suppresses cisplatin resistance of triple-negative breast cancer by inhibiting autophagy. Am. J. Med. Sci. 2025 369 2 252 263 10.1016/j.amjms.2024.08.012 39154963
    [Google Scholar]
  32. Di J. Bo W. Wang C. Liu C. Ailanthone increases cisplatin-induced apoptosis and autophagy in cisplatin resistance non-small cell lung cancer cells through the PI3K/AKT/mTOR Pathway. Curr. Med. Chem. 2024 10.2174/0109298673315460240816091032 39192653
    [Google Scholar]
  33. Al-Bahlani S. Al-Lawati H. Al-Adawi M. Al-Abri N. Al-Dhahli B. Al-Adawi K. Fatty acid synthase regulates the chemosensitivity of breast cancer cells to cisplatin-induced apoptosis. Apoptosis 2017 22 6 865 876 10.1007/s10495‑017‑1366‑2 28386750
    [Google Scholar]
  34. Lin Z. Liu H. Yang C. Zheng H. Zhang Y. Su W. Shang J. Curcumin mediates autophagy and apoptosis in granulosa cells: A study of integrated network pharmacology and molecular docking to elucidate toxicological mechanisms. Drug Chem. Toxicol. 2022 45 6 2411 2423 10.1080/01480545.2021.1956941 34315305
    [Google Scholar]
  35. Radin D. Lippa A. Patel P. Leonardi D. Lifeguard inhibition of Fas-mediated apoptosis: A possible mechanism for explaining the cisplatin resistance of triple-negative breast cancer cells. Biomed. Pharmacother. 2016 77 161 166 10.1016/j.biopha.2015.12.022 26796280
    [Google Scholar]
  36. Zhao Y. Jing Z. Li Y. Mao W. Berberine in combination with cisplatin suppresses breast cancer cell growth through induction of DNA breaks and caspase-3-dependent apoptosis. Oncol. Rep. 2016 36 1 567 572 10.3892/or.2016.4785 27177238
    [Google Scholar]
  37. Shi S. Tan P. Yan B. Gao R. Zhao J. Wang J. Guo J. Li N. Ma Z. ER stress and autophagy are involved in the apoptosis induced by cisplatin in human lung cancer cells. Oncol. Rep. 2016 35 5 2606 2614 10.3892/or.2016.4680 26985651
    [Google Scholar]
  38. Metge B.J. Mitra A. Chen D. Shevde L.A. Samant R.S. N-Myc and STAT Interactor regulates autophagy and chemosensitivity in breast cancer cells. Sci. Rep. 2015 5 1 11995 10.1038/srep11995 26146406
    [Google Scholar]
  39. Shen M. Duan W.M. Wu M.Y. Wang W.J. Liu L. Xu M.D. Zhu J. Li D.M. Gui Q. Lian L. Gong F.R. Chen K. Li W. Tao M. Participation of autophagy in the cytotoxicity against breast cancer cells by cisplatin. Oncol. Rep. 2015 34 1 359 367 10.3892/or.2015.4005 26005215
    [Google Scholar]
/content/journals/cmc/10.2174/0109298673379638250707061138
Loading
Polysaccharides from Sepia Esculenta Ink Promote Apoptosis via Inhibition of Autophagy in Cisplatin-exposed Triple-Negative Breast Cancer Cells
Bentham Science Publishers ; https://doi.org/10.2174/0109298673379638250707061138
/content/journals/cmc/10.2174/0109298673379638250707061138
/content/journals/cmc/10.2174/0109298673379638250707061138
Loading

Data & Media loading...


  • Article Type:     Research Article
Keywords: autophagy ; TNBC cells ; MDA-MB-231 cells ; Polysaccharides from sepia ink ; apoptosis ; cisplatin

Most Cited Most Cited RSS feed

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error
Please enter a valid_number test