Article | Published:

Acetyl-11-keto-β-boswellic acid suppresses docetaxel-resistant prostate cancer cells in vitro and in vivo by blocking Akt and Stat3 signaling, thus suppressing chemoresistant stem cell-like properties

Acta Pharmacologica Sinicavolume 40pages689698 (2019) | Download Citation

Subjects

Abstract

Acquired docetaxel-resistance of prostate cancer (PCa) remains a clinical obstacle due to the lack of effective therapies. Acetyl-11-keto-β-boswellic acid (AKBA) is a pentacyclic triterpenic acid isolated from the fragrant gum resin of the Boswellia serrata tree, which has shown intriguing antitumor activity against human cell lines established from PCa, colon cancer, malignant glioma, and leukemia. In this study, we examined the effects of AKBA against docetaxel-resistant PCa in vitro and in vivo as well as its anticancer mechanisms. We showed that AKBA dose-dependently inhibited cell proliferation and induced cell apoptosis in docetaxel-resistant PC3/Doc cells; its IC50 value in anti-proliferation was 17 μM. Furthermore, AKBA dose-dependently suppressed the chemoresistant stem cell-like properties of PC3/Doc cells, evidenced by significant decrease in the ability of mammosphere formation and down-regulated expression of a number of stemness-associated genes. The activation of Akt and Stat3 signaling pathways was remarkably enhanced in PC3/Doc cells, which contributed to their chemoresistant stem-like phenotype. AKBA (10–30 μM) dose-dependently suppressed the activation of Akt and Stat3 signaling pathways in PC3/Doc cells. In contrast, overexpression of Akt and Stat3 significantly attenuated the inhibition of AKBA on PC3/Doc cell proliferation. In docetaxel-resistant PCa homograft mice, treatment with AKBA significantly suppresses the growth of homograft RM-1/Doc, equivalent to its human PC3/Doc, but did not decrease their body weight. In summary, we demonstrate that AKBA inhibits the growth inhibition of docetaxel-resistant PCa cells in vitro and in vivo via blocking Akt and Stat3 signaling, thus suppressing their cancer stem cell-like properties.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

References

  1. 1.

    Siegel RL, Miller KD, Jemal A. Cancer statistics, 2016. CA Cancer J Clin. 2016;66:7–30.

  2. 2.

    Petrylak DP, Tangen CM, Hussain MH, Lara PN Jr, Jones JA, Taplin ME, et al. Docetaxel and estramustine compared with mitoxantrone and prednisone for advanced refractory prostate cancer. N Engl J Med. 2004;351:1513–20.

  3. 3.

    McKeage K. Docetaxel: a review of its use for the first-line treatment of advanced castration-resistant prostate cancer. Drugs. 2012;72:1559–77.

  4. 4.

    Mahon KL, Henshall SM, Sutherland RL, Horvath LG. Pathways of chemotherapy resistance in castration-resistant prostate cancer. Endocr Relat Cancer. 2011;18:R103–23.

  5. 5.

    Seruga B, Ocana A, Tannock IF. Drug resistance in metastatic castration resistant prostate cancer. Nat Rev Clin Oncol. 2011;8:12–23.

  6. 6.

    Ranganathan S, Benetatos CA, Colarusso PJ, Dexter DW, Hudes GR. Altered beta-tubulin isotype expression in paclitaxel resistant human prostate carcinoma cells. Br J Cancer. 1998;77:562–6.

  7. 7.

    Takeda M, Mizokami A, Mamiya K, Li YQ, Zhang J, Keller ET, et al. The establishment of two paclitaxel-resistant prostate cancer cell lines and the mechanisms of paclitaxel resistance with two cell lines. Prostate. 2007;67:955–67.

  8. 8.

    Zalcberg J, Hu XF, Slater A, Parisot J, El-Osta S, Kantharidis P, et al. MRP1 not MDR1 gene expression is the predominant mechanism of acquired multidrug resistance in two prostate carcinoma cell lines. Prostate Cancer Prostatic Dis. 2000;3:66–75.

  9. 9.

    Visvader JE, Lindeman GJ. Cancer stem cells in solid tumours: accumulating evidence and unresolved questions. Nat Rev Cancer. 2008;8:755–68.

  10. 10.

    Mimeault M, Hauke R, Mehta PP, Batra SK. Recent advances in cancer stem/progenitor cell research: therapeutic implications for overcoming resistance to the most aggressive cancers. J Cell Mol Med. 2007;11:981–1011.

  11. 11.

    Ni J, Cozzi P, Hao J, Duan W, Graham P, Kearsley J, et al. Cancer stem cells in prostate cancer chemoresistance. Curr Cancer Drug Targets. 2014;14:225–40.

  12. 12.

    Sell S. Cancer and stem cell signaling: a guide to preventive and therapeutic strategies for cancer stem cells. Stem Cell Rev. 2007;3:1–6.

  13. 13.

    Barr MP, Gray SG, Hoffmann AC, Hilger RA, Thomale J, O’Flaherty JD, et al. Generation and characterisation of cisplatin-resistant non-small cell lung cancer cell lines displaying a stem-like signature. PLoS ONE. 2013;8:e54193.

  14. 14.

    Lu LL, Chen XH, Zhang G, Liu ZC, Wu N, Wang H, et al. CCL21 facilitates chemoresistance and cancer stem cell-like properties of colorectal cancer cells through AKT/GSK-3. Oxid Med Cell Longev. 2016;2016:5874127.

  15. 15.

    Rybak AP, Bristow RG, Kapoor A. Prostate cancer stem cells: deciphering the origins and pathways involved in prostate tumorigenesis and aggression. Oncotarget. 2015;6:1900–19.

  16. 16.

    Maitland NJ, Collins AT. Prostate cancer stem cells: a new target for therapy. J Clin Oncol. 2008;26:2862–70.

  17. 17.

    Domingo-Domenech J, Vidal SJ, Rodriguez-Bravo V, Castillo-Martin M, Quinn SA, Rodriguez-Barrueco R, et al. Suppression of acquired docetaxel resistance in prostate cancer through depletion of notch- and hedgehog-dependent tumor-initiating cells. Cancer Cell. 2012;22:373–88.

  18. 18.

    Singh RK, Dhadve A, Sakpal A, De A, Ray P. An active IGF-1R-AKT signaling imparts functional heterogeneity in ovarian CSC population. Sci Rep. 2016;6:36612.

  19. 19.

    Singh RK, Gaikwad SM, Jinager A, Chaudhury S, Maheshwari A, Ray P, et al. IGF-1R inhibition potentiates cytotoxic effects of chemotherapeutic agents in early stages of chemoresistant ovarian cancer cells. Cancer Lett. 2014;354:254–62.

  20. 20.

    Qu Y, Oyan AM, Liu R, Hua Y, Zhang J, Hovland R, et al. Generation of prostate tumor-initiating cells is associated with elevation of reactive oxygen species and IL-6/STAT3 signaling. Cancer Res. 2013;73:7090–100.

  21. 21.

    Kroon P, Berry PA, Stower MJ, Rodrigues G, Mann VM, Simms M, et al. JAK-STAT blockade inhibits tumor initiation and clonogenic recovery of prostate cancer stem-like cells. Cancer Res. 2013;73:5288–98.

  22. 22.

    Abdel-Tawab M, Werz O, Schubert-Zsilavecz M. Boswellia serrata: an overall assessment of in vitro, preclinical, pharmacokinetic and clinical data. Clin Pharmacokinet. 2011;50:349–69.

  23. 23.

    Syrovets T, Buchele B, Krauss C, Laumonnier Y, Simmet T. Acetyl-boswellic acids inhibit lipopolysaccharidemediated TNF-α induction in monocytes by direct interaction with IκB kinases. J Immunol. 2005;174:498–506.

  24. 24.

    Syrovets T, Gschwend JE, Buchele B, Laumonnier Y, Zugmaier W, Genze F, et al. Inhibition of IkappaB kinase activity by acetyl-boswellic acids promotes apoptosis in androgen-independent PC-3 prostate cancer cells in vitro and in vivo. J Biol Chem. 2005;280:6170–80.

  25. 25.

    Liu JJ, Nilsson A, Oredsson S, Badmaev V, Zhao WZ, Duan RD. Boswellic acids trigger apoptosis via a pathway dependent on caspase-8 activation but independent on Fas/Fas ligand interaction in colon cancer HT-29 cells. Carcinogenesis. 2002;23:2087–93.

  26. 26.

    Hostanska K, Daum G, Saller R. Cytostatic and apoptosis-inducing activity of boswellic acids toward malignant cell lines in vitro. Anticancer Res. 2002;22:2853–62.

  27. 27.

    Zhang D, Cui Y, Niu L, Xu X, Tian K, Young CY, et al. Regulation of SOD2 and β-arrestin1 by interleukin-6 contributes to the increase of IGF-1R expression in docetaxel resistant prostate cancer cells. Eur J Cell Biol. 2014;93:289–98.

  28. 28.

    Xu Q, Liu X, Zhu S, Hu X, Niu H, Zhang X, et al. Hyper-acetylation contributes to the sensitivity of chemo-resistant prostatecancer cells to histone deacetylase inhibitor Trichostatin A. J Cell Mol Med. 2018;22:1909–22.

  29. 29.

    Yuan HQ, Kong F, Wang XL, Young CY, Hu XY, Lou HX. Inhibitory effect of acetyl-11-keto-beta-boswellic acid on androgen receptor by interference of Sp1 binding activity in prostate cancer cells. Biochem Pharmacol. 2008;75:2112–21.

  30. 30.

    Liu YQ, Hu XY, Lu T, Cheng YN, Young CY, Yuan HQ, et al. Retigeric acid B exhibits antitumor activity through suppression of nuclear factor-κB signaling in prostate cancer cells in vitro and in vivo. PLoS ONE. 2012;7:e38000.

  31. 31.

    Jiang H, Sun J, Xu Q, Liu Y, Wei J, Young CY, et al. Marchantin M: a novel inhibitor of proteasome induces autophagic cell death in prostate cancer cells. Cell Death Dis. 2013;4:e761.

  32. 32.

    Thompson TC, Southgate J, Kitchener G, Land H. Multistage carcinogenesis induced by ras and myc oncogenes in a reconstituted organ. Cell. 1989;56:917–30.

  33. 33.

    Achuthan S, Santhoshkumar TR, Prabhakar J, Nair SA, Pillai MR. Drug-induced senescence generates chemoresistant stemlike cells with low reactive oxygen species. J Biol Chem. 2011;286:37813–29.

  34. 34.

    Brambrink T, Foreman R, Welstead GG, Lengner CJ, Wernig M, Suh H, et al. Sequential expression of pluripotency markers during direct reprogramming of mouse somatic cells. Cell Stem Cell. 2008;2:151–9.

  35. 35.

    Zhao H, Guo Y, Li S, Han R, Ying J, Zhu H, et al. A novel anti-cancer agent Icaritin suppresses hepatocellular carcinomainitiation and malignant growth through the IL-6/Jak2/Stat3 pathway. Oncotarget. 2015;31:31927–43.

  36. 36.

    Ruefli AA, Bernhard D, Tainton KM, Kofler R, Smyth MJ, Johnstone RW. Suberoylanilide hydroxamic acid (SAHA) overcomes multidrug resistance and induces cell death in P-glycoprotein-expressing cells. Int J Cancer. 2002;99:292–8.

  37. 37.

    Xue X, Chen F, Liu A, Sun D, Wu J, Kong F, et al. Reversal of the multidrug resistance of human ileocecal adenocarcinoma cells by acetyl-11-keto-β-boswellic acid via downregulation of P-glycoprotein signals. Biosci Trends. 2016;10:392–9.

  38. 38.

    O’Neill AJ, Prencipe M, Dowling C, Fan Y, Mulrane L, Gallagher WM, et al. Characterisation and manipulation of docetaxel resistant prostate cancer cell lines. Mol Cancer. 2011;10:126.

  39. 39.

    Singh S, Trevino J, Bora-Singhal N, Coppola D, Haura E, Altiok S, et al. EGFR/Src/Akt signaling modulates Sox2 expression and self-renewal of stem-like side-population cells in non-small cell lung cancer. Mol Cancer. 2012;11:73.

  40. 40.

    McCubrey JA, Steelman LS, Abrams SL, Lee JT, Chang F, Bertrand FE, et al. Roles of the RAF/MEK/ERK and PI3K/PTEN/AKT pathways in malignant transformation and drug resistance. Adv Enzyme Regul. 2006;46:249–79.

  41. 41.

    Jeong CH, Cho YY, Kim MO, Kim SH, Cho EJ, Lee SY, et al. Phosphorylation of Sox2 cooperates in reprogramming to pluripotent stem cells. Stem Cells. 2010;28:2141–50.

  42. 42.

    Liu HP, Gao ZH, Cui SX, Wang Y, Li BY, Lou HX, et al. Chemoprevention of intestinal adenomatous polyposis by acetyl-11-keto-beta-boswellic acid in APC(Min/+) mice. Int J Cancer. 2013;132:2667–81.

  43. 43.

    Civenni G, Longoni N, Costales P, Dallavalle C, García Inclán C, Albino D, et al. EC-70124, a novel glycosylated indolocarbazole multi-kinase inhibitor, reverts tumorigenic and stem cell properties in prostate cancer by inhibiting STAT3 and NF-κB. Mol Cancer Ther. 2016;15:806–18.

Download references

Acknowledgements

This work was supported by the National Natural Science Foundation of China (Grant No. 81603140), Shandong Provincial Natural Science Foundation, China (Doctoral Foundation; Grant No. ZR2016HB69), Jinan Science and Technology Development Program (201704087), and Shandong Medicine and Health Science Technology (2017WS628, 2017WS202).

Author contributions

HXL, RMW, and YQL designed the research. YQL, QQX, YXG, and ZML performed the experiments. YQL, HXL, and HQY contributed new reagents and analytic tools. SKW, FK, and QW analyzed the data. YQL Liu wrote the paper.

Author information

Affiliations

  1. Department of Pharmacy, The Second Hospital of Shandong University, Jinan, 250033, China

    • Yong-qing Liu
    • , De-qing Sun
    •  & Rong-mei Wang
  2. Department of Natural Product Chemistry, School of Pharmaceutical Sciences, Shandong University, Jinan, 250012, China

    • Yong-qing Liu
    •  & Hong-xiang Lou
  3. Emergency Center, Shandong Provincial Hospital affiliated to Shandong University, Jinan, 250021, China

    • Shi-kang Wang
  4. Department of Dermato-venereology, The Second Hospital of Shandong University, Jinan, 250033, China

    • Qing-qing Xu
  5. Central Research Laboratory, The Second Hospital of Shandong University, Jinan, 250033, China

    • Qing-qing Xu
    • , Hui-qing Yuan
    • , Yan-xia Guo
    • , Feng Kong
    •  & Zhao-min Lin
  6. Department of Biochemistry and Molecular Biology, School of Medicine, Shandong University, Jinan, 250012, China

    • Qing-qing Xu
    • , Hui-qing Yuan
    •  & Qian Wang

Authors

  1. Search for Yong-qing Liu in:

  2. Search for Shi-kang Wang in:

  3. Search for Qing-qing Xu in:

  4. Search for Hui-qing Yuan in:

  5. Search for Yan-xia Guo in:

  6. Search for Qian Wang in:

  7. Search for Feng Kong in:

  8. Search for Zhao-min Lin in:

  9. Search for De-qing Sun in:

  10. Search for Rong-mei Wang in:

  11. Search for Hong-xiang Lou in:

Competing interests

The authors declare no competing interests.

Corresponding authors

Correspondence to Rong-mei Wang or Hong-xiang Lou.

Electronic supplementary material

About this article

Publication history

Received

Accepted

Published

Issue Date

DOI

https://doi.org/10.1038/s41401-018-0157-9