Skip to main content

Advertisement

SpringerLink
Log in

OSW-1 induces apoptosis and cyto-protective autophagy, and synergizes with chemotherapy on triple negative breast cancer metastasis

  • Original Article
  • Published:
Cellular Oncology Aims and scope Submit manuscript

Abstract

Purpose

Triple-negative breast cancer (TNBC) is the most malignant subtype of breast cancer. As yet, chemotherapy with drugs such as doxorubicin is the main treatment strategy. However, drug resistance and dose-dependent toxicities restrict their clinical use. Natural products are major sources of anti-tumor drugs. OSW-1 is a natural compound with strong anti-cancer effects in several types of cancer, but its effects on the efficacy of chemotherapy in TNBC and its underlying mechanism remain unclear.

Methods

The inhibitory activities of OSW-1 and its combination with several chemotherapy drugs were tested using in vitro assays and in vivo subcutaneous and metastatic mouse TNBC models. The effects of the mono- and combination treatments on TNBC cell viability, apoptosis, autophagy and related signaling pathways were assessed using MTT, flow cytometry, RNA sequencing and immunology-based assays. In addition, the in vivo inhibitory effects of OSW-1 and (combined) chemotherapies were evaluated in subcutaneous and metastatic mouse tumor models.

Results

We found that OSW-1 induces Ca2+-dependent mitochondria-dependent intrinsic apoptosis and cyto-protective autophagy through the PI3K-Akt-mTOR pathway in TNBC cells in vitro. We also found that OSW-1 and doxorubicin exhibited strong synergistic anti-TNBC capabilities both in vivo and in vitro. Combination treatment strongly inhibited spontaneous and experimental lung metastases in 4T1 mouse models. In addition, the combination strategy of OSW-1 + Carboplatin + Docetaxel showed an excellent anti-metastatic effect in vivo.

Conclusions

Our data revealed the mode of action and molecular mechanism underlying the effect of OSW-1 against TNBC, and provided a useful guidance for improving the sensitivity of TNBC cells to conventional chemotherapeutic drugs, which warrants further investigation.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9
Fig. 10

Similar content being viewed by others

Availability of data and materials

The raw data supporting the conclusions of this manuscript will be made available by the authors, without undue reservation, to any qualified researcher.

Abbreviations

TNBC:

Triple-negative breast cancer

DOX:

Doxorubicin hydrochloride

MTT:

3-(4,5- Dimethyllthiazole-2-yl)-2,5-diphenyltetrazolium bromide

DMSO:

Dimethyl sulfoxide

FCM:

Flow cytometry

ΔΨm:

Mitochondrial membrane potential

DMEM:

Dulbecco's modified eagle medium

Rh123:

3,6-Diamino-9-[2-(methoxycarbonyl)phenyl] xanthylium chloride

PRAP:

Poly ADP-ribose polymerase

Bcl-2:

B-cell lymphoma 2

CQ:

Chloroquine disphosphate

DAPI:

4′ 6-Diamidino-2-phenylindole

TME:

Tumor microenvironment

CBP:

Carboplatin

DOC:

Docetaxel

CI:

Chou-Talalay's combination index

IHC:

Immunohistochemistry

IAPs:

The inhibitor of apoptosis proteins

BIR:

Baculoviral IAP repeat

References

  1. R.L. Siegel, K.D. Miller, H.E. Fuchs, A. Jemal, Cancer Statistics, 2021. CA Cancer J. Clin. 71, 7–33 (2021)

    Article  Google Scholar 

  2. M.A. Thorat, R. Balasubramanian, Breast cancer prevention in high-risk women. Best Pract. Res. Clin. Obstet. Gynaecol. 65, 18–31 (2020)

    Article  Google Scholar 

  3. L. Fan, K. Strasser-Weippl, J.-J. Li, J. St Louis, D.M. Finkelstein, K.-D. Yu, W.-Q. Chen, Z.-M. Shao, P.E. Goss, Breast cancer in China. Lancet Oncol. 15, e279–e289 (2014)

    Article  Google Scholar 

  4. A.G. Waks, E.P. Winer, Breast cancer treatment: A review. JAMA 321, 288–300 (2019)

    Article  CAS  Google Scholar 

  5. L. Jin, B. Han, E. Siegel, Y. Cui, A. Giuliano, X. Cui, Breast cancer lung metastasis: Molecular biology and therapeutic implications. Cancer Biol. Ther. 19, 858–868 (2018)

    Article  CAS  Google Scholar 

  6. S. Lei, R. Zheng, S. Zhang, R. Chen, S. Wang, K. Sun, H. Zeng, W. Wei, J. He, Breast cancer incidence and mortality in women in China: temporal trends and projections to 2030. Cancer Biol. Med. (2021)

  7. W. Zhang, J.H. Mao, W. Zhu, A.K. Jain, K. Liu, J.B. Brown, G.H. Karpen, Centromere and kinetochore gene misexpression predicts cancer patient survival and response to radiotherapy and chemotherapy. Nat. Commun. 7, 12619 (2016)

    Article  CAS  Google Scholar 

  8. S. Rivankar, An overview of doxorubicin formulations in cancer therapy. J. Cancer Res. Ther. 10, 853–858 (2014)

    Article  Google Scholar 

  9. Y. Bao, M. Yin, X. Hu, X. Zhuang, Y. Sun, Y. Guo, S. Tan, Z. Zhang, A safe, simple and efficient doxorubicin prodrug hybrid micelle for overcoming tumor multidrug resistance and targeting delivery. J. Control Release. 235, 182–194 (2016)

    Article  CAS  Google Scholar 

  10. C. Holohan, S. Van Schaeybroeck, D.B. Longley, P.G. Johnston, Cancer drug resistance: an evolving paradigm. Nat. Rev. Cancer. 13, 714–726 (2013)

    Article  CAS  Google Scholar 

  11. H.S. Al-Malky, S.E. Al Harthi, A.M. Osman, Major obstacles to doxorubicin therapy: Cardiotoxicity and drug resistance. J. Oncol. Pharm. Pract. 26, 434–444 (2020)

    Article  Google Scholar 

  12. A. Dayton, K. Selvendiran, S. Meduru, M. Khan, M.L. Kuppusamy, S. Naidu, T. Kalai, K. Hideg, P. Kuppusamy, Amelioration of doxorubicin-induced cardiotoxicity by an anticancer-antioxidant dual-function compound, HO-3867. J. Pharmacol. Exp. Ther. 339, 350–357 (2011)

    Article  CAS  Google Scholar 

  13. S. Liu, R. Li, J. Qian, J. Sun, G. Li, J. Shen, Y. Xie, Combination therapy of Doxorubicin and Quercetin on multidrug-resistant breast cancer and their sequential delivery by reduction-sensitive hyaluronic acid-based conjugate/d-alpha-tocopheryl poly(ethylene glycol) 1000 succinate mixed micelles. Mol. Pharm. 17, 1415–1427 (2020)

    Article  CAS  Google Scholar 

  14. T. Iguchi, M. Kuroda, R. Naito, T. Watanabe, Y. Matsuo, A. Yokosuka, Y. Mimaki, Cholestane glycosides from Ornithogalum saundersiae bulbs and the induction of apoptosis in HL-60 cells by OSW-1 through a mitochondrial-independent signaling pathway. J. Nat. Med. 73, 131–145 (2019)

    Article  CAS  Google Scholar 

  15. Y. Zhou, C. Garcia-Prieto, D.A. Carney, R.H. Xu, H. Pelicano, Y. Kang, W. Yu, C. Lou, S. Kondo, J. Liu, D.M. Harris, Z. Estrov, M.J. Keating, Z. Jin, P. Huang, OSW-1: a natural compound with potent anticancer activity and a novel mechanism of action. J. Natl. Cancer Inst. 97, 1781–1785 (2005)

    Article  CAS  Google Scholar 

  16. J. Jin, X. Jin, C. Qian, Y. Ruan, H. Jiang, Signaling network of OSW1induced apoptosis and necroptosis in hepatocellular carcinoma. Mol. Med. Rep. 7, 1646–1650 (2013)

    Article  CAS  Google Scholar 

  17. Y. Zhang, F. Fang, K. Fan, Y. Zhang, J. Zhang, H. Guo, P. Yu, J. Ma, Effective cytotoxic activity of OSW-1 on colon cancer by inducing apoptosis in vitro and in vivo. Oncol. Rep. 37, 3509–3519 (2017)

    Article  CAS  Google Scholar 

  18. J. Maj, J.W. Morzycki, L. Rárová, J. Oklešt’ková, M. Strnad, A. Wojtkielewicz, Synthesis and biological activity of 22-deoxo-23-oxa analogues of saponin OSW-1. J. Med. Chem. 54, 3298–3305 (2011)

    Article  CAS  Google Scholar 

  19. J. Jin, X. Jin, C. Qian, Y. Ruan, H. Jiang, Signaling network of OSW-1-induced apoptosis and necroptosis in hepatocellular carcinoma. Mol. Med. Rep. 7, 1646–1650 (2013)

    Article  CAS  Google Scholar 

  20. J.C. Jin, X.L. Jin, X. Zhang, Y.S. Piao, S.P. Liu, Effect of OSW-1 on microRNA expression profiles of hepatoma cells and functions of novel microRNAs. Mol. Med. Rep. 7, 1831–1837 (2013)

    Article  CAS  Google Scholar 

  21. A.W. Burgett, T.B. Poulsen, K. Wangkanont, D.R. Anderson, C. Kikuchi, K. Shimada, S. Okubo, K.C. Fortner, Y. Mimaki, M. Kuroda, J.P. Murphy, D.J. Schwalb, E.C. Petrella, I. Cornella-Taracido, M. Schirle, J.A. Tallarico, M.D. Shair, Natural products reveal cancer cell dependence on oxysterol-binding proteins. Nat. Chem. Biol. 7, 639–647 (2011)

    Article  CAS  Google Scholar 

  22. R.C. Bensen, G. Gunay, M.C. Finneran, I. Jhingan, H. Acar, A.W.G. Burgett, Small molecule targeting of oxysterol-binding protein (OSBP)-related protein 4 and OSBP inhibits ovarian cancer cell prolifesation in monolayer and spheroid cell models. ACS Pharm. Transl. Sci. 4, 744–756 (2021)

    Article  CAS  Google Scholar 

  23. X. Ding, Y. Li, J. Li, Y. Yin, OSW-1 inhibits tumor growth and metastasis by NFATc2 on triple-negative breast cancer. Cancer Med. 9, 5558–5569 (2020)

    Article  CAS  Google Scholar 

  24. C. Garcia-Prieto, K.B. Riaz Ahmed, Z. Chen, Y. Zhou, N. Hammoudi, Y. Kang, C. Lou, Y. Mei, Z. Jin, P. Huang, Effective killing of leukemia cells by the natural product OSW-1 through disruption of cellular calcium homeostasis. J. Biol. Chem. 288, 3240–3250 (2013)

    Article  CAS  Google Scholar 

  25. M. Kimura, K. Sasaki, Y. Fukutani, H. Yoshida, I. Ohsawa, M. Yohda, K. Sakurai, Anticancer saponin OSW-1 is a novel class of selective Golgi stress inducer. Bioorg. Med. Chem. Lett. 29, 1732–1736 (2019)

    Article  CAS  Google Scholar 

  26. Q. Sun, X. Yu, C. Peng, N. Liu, W. Chen, H. Xu, H. Wei, K. Fang, Z. Dong, C. Fu, Y. Xu, W. Lu, Activation of SREBP-1c alters lipogenesis and promotes tumor growth and metastasis in gastric cancer. Biomed. Pharmacother. 128, 110274 (2020)

    Article  CAS  Google Scholar 

  27. Y. Xia, F. Xu, M. Xiong, H. Yang, W. Lin, Y. Xie, H. Xi, Q. Xue, T. Ye, L. Yu, Repurposing of antipsychotic trifluoperazine for treating brain metastasis, lung metastasis and bone metastasis of melanoma by disrupting autophagy flux. Pharmacol. Res. 163, 105295 (2021)

    Article  CAS  Google Scholar 

  28. J. Xia, Y. Inagaki, J. Gao, F. Qi, P. Song, G. Han, T. Sawakami, B. Gao, C. Luo, N. Kokudo, K. Hasegawa, Y. Sakamoto, W. Tang, Combination of cinobufacini and doxorubicin increases apoptosis of hepatocellular carcinoma cells through the Fas- and mitochondria-mediated pathways. Am. J. Chin. Med. 45, 1537–1556 (2017)

    Article  CAS  Google Scholar 

  29. T.C. Chou, Theoretical basis, experimental design, and computerized simulation of synergism and antagonism in drug combination studies. Pharmacol. Rev. 58, 621–681 (2006)

    Article  CAS  Google Scholar 

  30. Y. Xia, C. Jia, Q. Xue, J. Jiang, Y. Xie, R. Wang, Z. Ran, F. Xu, Y. Zhang, T. Ye, Antipsychotic drug trifluoperazine suppresses colorectal cancer by inducing G0/G1 arrest and apoptosis. Front. Pharmacol. 10, 1029 (2019)

    Article  CAS  Google Scholar 

  31. N. Liu, Q. Sun, H. Xu, X. Yu, W. Chen, H. Wei, J. Jiang, Y. Xu, W. Lu, Hyperuricemia induces lipid disturbances mediated by LPCAT3 upregulation in the liver. FASEB J. 34, 13474–13493 (2020)

    Article  CAS  Google Scholar 

  32. X.L. Luo, L. Lin, H. Hu, F.L. Hu, Y. Lin, M.L. Luo, L. Wang, Y.Q. He, Development and characterization of mammary intraductal (MIND) spontaneous metastasis models for triple-negative breast cancer in syngeneic mice. Sci. Rep. 10, 4681 (2020)

    Article  CAS  Google Scholar 

  33. V.L. Silva, D. Ferreira, F.L. Nobrega, I.M. Martins, L.D. Kluskens, L.R. Rodrigues, Selection of novel peptides homing the 4T1 cell line: Exploring alternative targets for triple negative breast cancer. PLoS ONE 11, e0161290 (2016)

    Article  Google Scholar 

  34. K. Wang, T. Zhang, Y. Lei, X. Li, J. Jiang, J. Lan, Y. Liu, H. Chen, W. Gao, N. Xie, Q. Chen, X. Zhu, X. Liu, K. Xie, Y. Peng, E.C. Nice, M. Wu, C. Huang, Y. Wei, Identification of ANXA2 (annexin A2) as a specific bleomycin target to induce pulmonary fibrosis by impeding TFEB-mediated autophagic flux. Autophagy 14, 269–282 (2018)

    Article  CAS  Google Scholar 

  35. Y. Shi, Mechanisms of caspase activation and inhibition during apoptosis. Mol. Cell. 9, 459–470 (2002)

    Article  CAS  Google Scholar 

  36. A. Gross, J.M. McDonnell, S.J. Korsmeyer, BCL-2 family members and the mitochondria in apoptosis. Genes Dev. 13, 1899–1911 (1999)

    Article  CAS  Google Scholar 

  37. S. Cory, D.C. Huang, J.M. Adams, The Bcl-2 family: roles in cell survival and oncogenesis. Oncogene 22, 8590–8607 (2003)

    Article  CAS  Google Scholar 

  38. A. Shamas-Din, J. Kale, B. Leber, D.W. Andrews, Mechanisms of action of Bcl-2 family proteins. Cold Spring Harb. Perspect. Biol. 5, a008714 (2013)

    Article  Google Scholar 

  39. K. Wang, R. Liu, J. Li, J. Mao, Y. Lei, J. Wu, J. Zeng, T. Zhang, H. Wu, L. Chen, C. Huang, Y. Wei, Quercetin induces protective autophagy in gastric cancer cells: involvement of Akt-mTOR- and hypoxia-induced factor 1α-mediated signaling. Autophagy 7, 966–978 (2011)

    Article  CAS  Google Scholar 

  40. G.S. Salvesen, C.S. Duckett, IAP proteins: blocking the road to death’s door. Nat. Rev. Mol. Cell Biol. 3, 401–410 (2002)

    Article  CAS  Google Scholar 

  41. Y. Wei, T. Fan, M. Yu, Inhibitor of apoptosis proteins and apoptosis. Acta Biochim. Biophys. Sinica. 40, 278–288 (2008)

    Article  Google Scholar 

  42. G. Song, G. Ouyang, S. Bao, The activation of Akt/PKB signaling pathway and cell survival. J. Cell. Mol. Med. 9, 59–71 (2005)

    Article  CAS  Google Scholar 

  43. B.L. Roberts, Z.C. Severance, R.C. Bensen, A.T. Le, N.R. Kothapalli, J.I. Nunez, H. Ma, S. Wu, S.J. Standke, Z. Yang, W.J. Reddig, E.L. Blewett, A.W.G. Burgett, Transient compound treatment induces a multigenerational reduction of oxysterol-binding protein (OSBP) levels and rophylactic antiviral activity. ACS Chem. Biol. 14, 276–287 (2019)

    Article  CAS  Google Scholar 

  44. T. Sharif, E. Martell, C. Dai, M.S. Ghassemi-Rad, M.R. Hanes, P.J. Murphy, N.N. Margam, H.B. Parmar, C.A. Giacomantonio, R. Duncan, P.W.K. Lee, S. Gujar, HDAC6 differentially regulates autophagy in stem-like versus differentiated cancer cells. Autophagy 15, 686–706 (2019)

    Article  CAS  Google Scholar 

  45. C. Liu, L. Sun, J. Yang, T. Liu, Y. Yang, S.M. Kim, X. Ou, Y. Wang, L. Sun, M. Zaidi, M.I. New, T. Yuen, Q. Guo, FSIP1 regulates autophagy in breast cancer. Proc. Natl. Acad. Sci U. S. A. 115, 13075–13080 (2018)

    Article  CAS  Google Scholar 

  46. C.G. Kinsey, S.A. Camolotto, A.M. Boespflug, K.P. Guillen, M. Foth, A. Truong, S.S. Schuman, J.E. Shea, M.T. Seipp, J.T. Yap, L.D. Burrell, D.H. Lum, J.R. Whisenant, G.W. Gilcrease 3rd., C.C. Cavalieri, K.M. Rehbein, S.L. Cutler, K.E. Affolter, A.L. Welm, B.E. Welm, C.L. Scaife, E.L. Snyder, M. McMahon, Protective autophagy elicited by RAF→MEK→ERK inhibition suggests a treatment strategy for RAS-driven cancers. Nat. Med. 25, 620–627 (2019)

    Article  CAS  Google Scholar 

  47. A. González, M.N. Hall, Nutrient sensing and TOR signaling in yeast and mammals. EMBO J. 36, 397–408 (2017)

    Article  Google Scholar 

  48. R.A. Saxton, D.M. Sabatini, mTOR signaling in growth, metabolism, and disease. Cell 168, 960–976 (2017)

    Article  CAS  Google Scholar 

  49. K.K. Brown, J.B. Spinelli, J.M. Asara, A. Toker, Adaptive Reprogramming of de novo pyrimidine synthesis is a metabolic vulnerability in triple-negative breast cancer. Cancer Discov. 7, 391–399 (2017)

    Article  CAS  Google Scholar 

  50. S.L. Koppenhafer, K.L. Goss, W.W. Terry, D.J. Gordon, mTORC1/2 and protein translation regulate levels of CHK1 and the sensitivity to CHK1 inhibitors in Ewing sarcoma cells. Mol. Cancer Ther. 17, 2676–2688 (2018)

    Article  CAS  Google Scholar 

  51. M. Granato, C. Rizzello, M.A. Romeo, S. Yadav, R. Santarelli, G. D’Orazi, A. Faggioni, M. Cirone, Concomitant reduction of c-Myc expression and PI3K/AKT/mTOR signaling by quercetin induces a strong cytotoxic effect against Burkitt’s lymphoma. Int. J. Biochem. Cell Biol. 79, 393–400 (2016)

    Article  CAS  Google Scholar 

  52. M.A. Gregory, Y. Qi, S.R. Hann, Phosphorylation by glycogen synthase kinase-3 controls c-myc proteolysis and subnuclear localization. J. Biol. Chem. 278, 51606–51612 (2003)

    Article  CAS  Google Scholar 

  53. D. Alizadeh, M. Trad, N.T. Hanke, C.B. Larmonier, N. Janikashvili, B. Bonnotte, E. Katsanis, N. Larmonier, Doxorubicin eliminates myeloid-derived suppressor cells and enhances the efficacy of adoptive T-cell transfer in breast cancer. Cancer Res. 74, 104–118 (2014)

    Article  CAS  Google Scholar 

  54. T. Kitamura, B.Z. Qian, D. Soong, L. Cassetta, R. Noy, G. Sugano, Y. Kato, J. Li, J.W. Pollard, CCL2-induced chemokine cascade promotes breast cancer metastasis by enhancing retention of metastasis-associated macrophages. J. Exp. Med. 212, 1043–1059 (2015)

    Article  CAS  Google Scholar 

  55. J. Kim, J.S. Bae, Tumor-associated macrophages and neutrophils in tumor microenvironment. Mediators Inflamm. 2016, 6058147 (2016)

    Article  Google Scholar 

  56. N.Y. Sun, Y.L. Chen, H.W. Lin, Y.C. Chiang, C.F. Chang, Y.J. Tai, C.A. Chen, W.Z. Sun, C.L. Chien, W.F. Cheng, Immune checkpoint Ab enhances the antigen-specific anti-tumor effects by modulating both dendritic cells and regulatory T lymphocytes. Cancer Lett. 444, 20–34 (2019)

    Article  CAS  Google Scholar 

  57. T. Nosaka, T. Baba, Y. Tanabe, S. Sasaki, T. Nishimura, Y. Imamura, H. Yurino, S. Hashimoto, M. Arita, Y. Nakamoto, N. Mukaida, Alveolar macrophages drive hepatocellular carcinoma lung metastasis by generating leukotriene B4. J. Immunol. 200, 1839–1852 (2018)

    CAS  Google Scholar 

  58. F. Musa, A. Alard, G. David-West, J.P. Curtin, S.V. Blank, R.J. Schneider, Dual mTORC1/2 inhibition as a novel strategy for the resensitization and treatment of platinum-resistant ovarian cancer. Mol. Cancer Ther. 15, 1557–1567 (2016)

    Article  CAS  Google Scholar 

  59. G. David-West, A. Ernlund, A. Gadi, R.J. Schneider, mTORC1/2 inhibition re-sensitizes platinum-resistant ovarian cancer by disrupting selective translation of DNA damage and survival mRNAs. Oncotarget 9, 33064–33076 (2018)

    Article  Google Scholar 

  60. R.R. Braeuer, I.R. Watson, C.J. Wu, A.K. Mobley, T. Kamiya, E. Shoshan, M. Bar-Eli, Why is melanoma so metastatic? Pigment Cell Melanoma Res. 27, 19–36 (2014)

    Article  CAS  Google Scholar 

  61. D. Grandgirard, E. Studer, L. Monney, T. Belser, I. Fellay, C. Borner, M.R. Michel, Alphaviruses induce apoptosis in Bcl-2-overexpressing cells: evidence for a caspase-mediated, proteolytic inactivation of Bcl-2. EMBO J. 17, 1268–1278 (1998)

    Article  CAS  Google Scholar 

  62. E.H. Cheng, D.G. Kirsch, R.J. Clem, R. Ravi, M.B. Kastan, A. Bedi, K. Ueno, J.M. Hardwick, Conversion of Bcl-2 to a Bax-like death effector by caspases. Science (New York, N.Y.). 278, 1966–1968 (1997)

    Article  CAS  Google Scholar 

  63. Y.M. Kim, T.H. Kim, D.W. Seol, R.V. Talanian, T.R. Billiar, Nitric oxide suppression of apoptosis occurs in association with an inhibition of Bcl-2 cleavage and cytochrome c release. J. Biol. Chem. 273, 31437–31441 (1998)

    Article  CAS  Google Scholar 

  64. X. Saelens, N. Festjens, L. Vande Walle, M. van Gurp, G. van Loo, P. Vandenabeele, Toxic proteins released from mitochondria in cell death. Oncogene. 23, 2861–2874 (2004)

    Article  CAS  Google Scholar 

  65. R. Amaravadi, A.C. Kimmelman, E. White, Recent insights into the function of autophagy in cancer. Genes Dev. 30, 1913–1930 (2016)

    Article  CAS  Google Scholar 

  66. J.M.M. Levy, C.G. Towers, A. Thorburn, Targeting autophagy in cancer. Nat. Rev. Cancer. 17, 528–542 (2017)

    Article  CAS  Google Scholar 

  67. E. White, J.M. Mehnert, C.S. Chan, Autophagy, metabolism, and cancer. Clin. Cancer Res. 21, 5037–5046 (2015)

    Article  CAS  Google Scholar 

  68. P. Jiang, N. Mizushima, LC3- and p62-based biochemical methods for the analysis of autophagy progression in mammalian cells. Methods 75, 13–18 (2015)

    Article  CAS  Google Scholar 

  69. B. Pasquier, SAR405, a PIK3C3/Vps34 inhibitor that prevents autophagy and synergizes with MTOR inhibition in tumor cells. Autophagy 11, 725–726 (2015)

    Article  CAS  Google Scholar 

  70. R. Rangwala, Y.C. Chang, J. Hu, K.M. Algazy, T.L. Evans, L.A. Fecher, L.M. Schuchter, D.A. Torigian, J.T. Panosian, A.B. Troxel, K.S. Tan, D.F. Heitjan, A.M. DeMichele, D.J. Vaughn, M. Redlinger, A. Alavi, J. Kaiser, L. Pontiggia, L.E. Davis, P.J. O’Dwyer, R.K. Amaravadi, Combined MTOR and autophagy inhibition: phase I trial of hydroxychloroquine and temsirolimus in patients with advanced solid tumors and melanoma. Autophagy 10, 1391–1402 (2014)

    Article  CAS  Google Scholar 

  71. S. Wu, C. Sun, D. Tian, Y. Li, X. Gao, S. He, T. Li, Expression and clinical significances of Beclin1, LC3 and mTOR in colorectal cancer. Int. J. Clin. Exp. Pathol. 8, 3882–3891 (2015)

    Google Scholar 

  72. T.S. Beyett, C. To, D.E. Heppner, J.K. Rana, A.M. Schmoker, J. Jang, D.J.H. De Clercq, G. Gomez, D.A. Scott, N.S. Gray, P.A. Jänne, M.J. Eck, Molecular basis for cooperative binding and synergy of ATP-site and allosteric EGFR inhibitors. Nat. Comm. 13, 2530 (2022)

    Article  CAS  Google Scholar 

  73. M.J. Morgan, G. Gamez, C. Menke, A. Hernandez, J. Thorburn, F. Gidan, L. Staskiewicz, S. Morgan, C. Cummings, P. Maycotte, A. Thorburn, Regulation of autophagy and chloroquine sensitivity by oncogenic RAS in vitro is context-dependent. Autophagy 10, 1814–1826 (2014)

    Article  CAS  Google Scholar 

  74. H. Vakifahmetoglu-Norberg, H.G. Xia, J. Yuan, Pharmacologic agents targeting autophagy. J. Clin Invest. 125, 5–13 (2015)

    Article  Google Scholar 

  75. Z. Choo, A.H.P. Loh, Z.X. Chen, Destined to die: Apoptosis and pediatric cancers. Cancers. 11, (2019)

  76. J. Liu, Z. Zhao, N. Qiu, Q. Zhou, G. Wang, H. Jiang, Y. Piao, Z. Zhou, J. Tang, Y. Shen, Co-delivery of IOX1 and doxorubicin for antibody-independent cancer chemo-immunotherapy. Nat. Comm. 12, 2425 (2021)

    Article  CAS  Google Scholar 

  77. M. Wu, Q. Huang, Y. Xie, X. Wu, H. Ma, Y. Zhang, Y. Xia, Improvement of the anticancer efficacy of PD-1/PD-L1 blockade via combination therapy and PD-L1 regulation. J. Hematol. Oncol. 15, 24 (2022)

    Article  CAS  Google Scholar 

Download references

Funding

This work was supported by the National Natural Science Foundation of China (grant number 82173280), the Chengdu Science and Technology Bureau International Cooperation Project (grant number: 2019-GH02-00036-HZ), the Department of Science and Technology of Sichuan Province (grant number: 2021YJ0450), the Post-Doctor Research Project, West China Hospital, Sichuan University (Grant No. 2019HXBH017) and 135 project West China Hospital, Sichuan University (ZYJC21016).

Author information

Author notes

  1. Mengling Wu, Qianrui Huang and Mengya Liao contributed equally to this work.

Authors and Affiliations

  1. Department of Rehabilitation Medicine, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center for Biotherapy, Chengdu, 610041, China

    Mengling Wu, Qianrui Huang, Xuyi Wu, Huizhi Xi, Yiwen Zhang & Yong Xia

  2. Center of Gerontology and Geriatrics, West China Hospital, Sichuan University, Chengdu, 610041, China

    Mengya Liao

  3. West China School of Pharmacy, Sichuan University, Chengdu, 60041, China

    Hongbo Ma & Shanrui Li

  4. Key Laboratory of Rehabilitation Medicine in Sichuan Province/Rehabilitation Medicine Research Institute, Chengdu, 610041, China

    Yong Xia

Authors
  1. Mengling Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Qianrui Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Mengya Liao
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Xuyi Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Huizhi Xi
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Hongbo Ma
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Shanrui Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Yiwen Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Yong Xia
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

X–Y and Z-YW designed the study. X–Y and Z-YW supervised the study. W-ML, H-QR, W-XY, L-MY, X-HZ, M-HB and L-SR performed the experiments. W-ML and X–Y evaluated the data. W-ML and X–Y wrote the paper. The data and the manuscript have been discussed and approved by all authors.

Corresponding authors

Correspondence to Yiwen Zhang or Yong Xia.

Ethics declarations

Ethics approval and consent to participate

The animal experiments were carried out in accordance with the recommendations of the Ethics Committee of Sichuan University. The protocol was approved by the Ethics Committee of Sichuan University.

Consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

Additional information

Publisher's note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (DOCX 1897 KB)

Rights and permissions

Springer Nature or its licensor 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.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Wu, M., Huang, Q., Liao, M. et al. OSW-1 induces apoptosis and cyto-protective autophagy, and synergizes with chemotherapy on triple negative breast cancer metastasis. Cell Oncol. 45, 1255–1275 (2022). https://doi.org/10.1007/s13402-022-00716-2

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13402-022-00716-2

Keywords

Search

Navigation