Skip to main content

Advertisement

SpringerLink
Log in

Zunyimycin C inhibits the proliferation of lung cancer cells by inducing apoptosis through an AKT-related mechanism

  • Original Research
  • Published:
Medicinal Chemistry Research Aims and scope Submit manuscript

Abstract

Objective

Zunyimycin C is a novel halogenated type II polyketide derived from the fermentation product of the Streptomyces species with notable antibiotic activity. However, it is still unclear whether zunyimycin C could inhibit the activity of cancer cells. In this study, human lung adenocarcinoma cell line A549, the large-cell lung cancer cell line NCI-H460 and the non-small-cell lung cancer cell line NCI-H1299 were employed to determine the in vitro anticancer properties of zunyimycin C and underlying molecular mechanisms.

Materials and methods

The cellular viability and proliferative properties of lung cancer cells were investigated using the Cell Counting Kit-8 and colony formation assay, respectively. The mRNA expression of apoptotic genes related to lung cancer was studied using reverse-transcription polymerase chain reaction. The apoptotic ratio was measured through flow cytometry. The protein expression was visualized via western blotting using specific antibodies.

Results

Zunyimycin C could inhibit cell proliferation and induce apoptosis in a dose-dependent manner. The expression levels of apoptosis-related proteins (i.e., BAX, cleaved-caspase-3, and cleaved-caspase-9) were increased compared with the control group. However, the levels of Bcl-2 and phosphorylated AKT were decreased by administration by zunyimycin C.

Conclusions

Collectively, these results implied that zunyimycin C could inhibit cell proliferation and induce apoptosis via AKT phosphorylation.

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

Similar content being viewed by others

References

  • Ahn DS, Lee HJ, Hwang J et al. (2018) Lambertianic acid sensitizes non-small cell lung cancers to TRAIL-induced apoptosis via inhibition of XIAP/NF-κB and activation of caspases and death receptor 4. Int J Mol Sci 19(5):1476

    Article  PubMed Central  CAS  Google Scholar 

  • Andreu-Fernández V, Sancho M, Genovés A et al. (2017) Bax transmembrane domain interacts with prosurvival Bcl-2 proteins in biological membranes. Proc Natl Acad Sci USA 114(2):310–315

    Article  PubMed  CAS  Google Scholar 

  • Byers LA, Rudin CM (2015) Small cell lung cancer: where do we go from here? Cancer 121:664–672

    Article  CAS  PubMed  Google Scholar 

  • Barka EA, Vatsa P, Sanchez L et al. (2016) Taxonomy, physiology, and natural products of actinobacteria. Microbiol Mol Biol Rev 80(1):1–43

    Article  PubMed  Google Scholar 

  • Boichuk S, Lee DJ, Mehalek KR et al. (2014) Unbiased compound screening identifies unexpected drug sensitivities and novel treatment options for gastrointestinal stromal tumors. Cancer Res 74(4):1200–1213

    Article  CAS  PubMed  Google Scholar 

  • Booth LA, Tavallai S, Hamed HA et al. (2014) The role of cell signalling in the crosstalk between autophagy and apoptosis. Cell Signal 26(3):549–555

    Article  CAS  PubMed  Google Scholar 

  • Birkinshaw RW, Czabotar PE (2017) The BCL-2 family of proteins and mitochondrial outer membrane permeabilisation. Semin Cell Dev Biol 72:152–162

    Article  CAS  PubMed  Google Scholar 

  • Chen W, Zheng R, Baade PD et al. (2016) Cancer statistics in China, 2015. Cancer J Clin 66(2):115–132

    Article  Google Scholar 

  • Chen Y, Tang Q, Xiao Q et al. (2017) Targeting EP4 downstream c-Jun through ERK1/2-mediated reduction of DNMT1 reveals novel mechanism of solamargine inhibited growth of lung cancer cells. J Cell Mol Med 21:222–233

    Article  CAS  PubMed  Google Scholar 

  • Deben C, Lardon F, Wouters A et al. (2016) APR-246 (PRIMA-1(MET)) strongly synergizes with AZD2281 (olaparib) induced PARP inhibition to induce apoptosis in non-small cell lung cancer cell lines. Cancer Lett 375(2):313–322

    Article  CAS  PubMed  Google Scholar 

  • Fei HR, Tian H, Zhou XL et al. (2016) Inhibition of autophagy enhances effects of PF-04691502 on apoptosis and DNA damage of lung cancer cells. Int J Biochem Cell Biol 78:52–62

    Article  CAS  PubMed  Google Scholar 

  • Fouillaud M, Venkatachalam M, Girard-Valenciennes E et al. (2016) Anthraquinones and derivatives from marine-derived fungi: structural diversity and selected biological activities. Mar Drugs 14(4):64

    Article  PubMed Central  CAS  Google Scholar 

  • Franke TF (2008) PI3K/Akt: getting it right matters. Oncogene 27(50):6473–6488

    Article  CAS  PubMed  Google Scholar 

  • Guise CP, Mowday AM, Ashoorzadeh A et al. (2014) Bioreductive prodrugs as cancer therapeutics: targeting tumor hypoxia. Chin J Cancer 33(2):80–86

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hadjithomas M, Chen IA, Chu K et al. (2017) IMG-ABC: new features for bacterial secondary metabolism analysis and targeted biosynthetic gene cluster discovery in thousands of microbial genomes. Nucleic Acids Res 45(D1):D560–D565

    Article  CAS  PubMed  Google Scholar 

  • Hansakul P, Aree K, Tanuchit S, Itharat A (2014) Growth arrest and apoptosis via caspase activation of dioscoreanone in human non-small-cell lung cancer A549 cells. BMC Complement Altern Med 14:413

    Article  PubMed  PubMed Central  Google Scholar 

  • Hassan M, Watari H, AbuAlmaaty A et al. (2014) Apoptosis and molecular targeting therapy in cancer. Biomed Res Int 2014:150845

    PubMed  PubMed Central  Google Scholar 

  • Herman NA, Kim SJ, Li JS et al. (2017) The industrial anaerobe Clostridium acetobutylicum uses polyketides to regulate cellular differentiation. Nat Commun 8(1):1514

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Hong QY, Wu GM, Qian GS et al. (2015) Prevention and management of lung cancer in China. Cancer 121:3080–3088

    Article  PubMed  Google Scholar 

  • Hua F, Shang S, Hu ZW (2017) Seeking new anti-cancer agents from autophagy-regulating natural products. J Asian Nat Prod Res 19(4):305–313

    Article  CAS  PubMed  Google Scholar 

  • Jacobsen K, Bertran-Alamillo J, Molina MA et al. (2017) Convergent Akt activation drives acquired EGFR inhibitor resistance in lung cancer. Nat commun 8(1):410

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Kang Y, Wang ZJ, Xie D et al. (2017) Characterization and potential antitumor activity of polysaccharide from Gracilariopsis lemaneiformis. Mar Drugs 15(4):100

    Article  PubMed Central  CAS  Google Scholar 

  • Kawada M, Kawatsu M, Masuda T et al. (2003) Specific inhibitors of protein phosphatase 2A inhibit tumor metastasis through augmentation of natural killer cells. Int Immunopharmacol 3(2):179–188

    Article  CAS  PubMed  Google Scholar 

  • Kinghorn AD, DE Blanco EJ, Lucas DM et al. (2016) Discovery of anticancer agents of diverse natural origin. Anticancer Res 36(11):5623–5637

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kodali S, Galgoci A, Young K et al. (2005) Determination of selectivity and efficacy of fatty acid synthesis inhibitors. J Biol Chem 280(2):1669–1677

    Article  CAS  PubMed  Google Scholar 

  • Lü Y, Shao M, Wang Y et al. (2017) Zunyimycins B and C, new chloroanthrabenzoxocinones antibiotics against methicillin-resistant Staphylococcus aureus and Enterococci from Streptomyces sp. FJS31-2. Molecules 22(2):251

    Article  PubMed Central  CAS  Google Scholar 

  • Liu W, Christenson SD, Standage S, Shen B (2002) Biosynthesis of the enediyne antitumor antibiotic C-1027. Science 297(5584):1170–1173

    Article  CAS  PubMed  Google Scholar 

  • Li JS, Zhang H, Qi H et al. (2018) Bioactive naphthoquinone and anthrone derivatives from endophytic Micromonospora sp. NEAU-gq13. J Asian Nat Prod Res 26:1–10

    Google Scholar 

  • Li X, Zeng X, Sun J et al. (2014) Imperatorin induces Mcl-1 degradation to cooperatively trigger Bax translocation and Bak activation to suppress drug-resistant human hepatoma. Cancer Lett 348(1-2):146–155

    Article  CAS  PubMed  Google Scholar 

  • Lu C, Zhao Y, Jia WQ et al. (2017) A new anthracycline-type metabolite from Streptomyces sp. NEAU-L3. J Antibiot 70(10):1026–1028

    Article  CAS  Google Scholar 

  • Luo X, Luo W, Lin C et al. (2014) Andrographolide inhibits proliferation of human lung cancer cells and the related mechanisms. Int J Clin Exp Med 7:4220–4225

    PubMed  PubMed Central  Google Scholar 

  • Manning BD, Cantley LC (2007) AKT/PKB signaling: navigating downstream. Cell 129(3):1261–1274

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mei C, Zhou S, Zhu L et al. (2017) Antitumor effects of laminaria extract fucoxanthin on lung cancer. Mar Drugs 15(2):39

    Article  PubMed Central  CAS  Google Scholar 

  • Newman DJ, Cragg GM, Snader KM (2003) Natural products as sources of new drugs over the period 1981–2002. J Nat Prod 66:1022–1037

    Article  CAS  PubMed  Google Scholar 

  • Pan LL, Wang XL, Zhang QY et al. (2016) Boehmenan, a lignan from the Chinese medicinal plant Clematis armandii, induces apoptosis in lung cancer cells through modulation of EGF-dependent pathways. Phytomedicine 23(5):468–476

    Article  CAS  PubMed  Google Scholar 

  • Pinkhien T, Maiuthed A, Chamni S et al. (2016) Bishydroquinone renieramycin M induces apoptosis of human lung cancer cells through a mitochondria-dependent pathway. Anticancer Res 36(12):6327–6333

    Article  CAS  PubMed  Google Scholar 

  • Reyna DE, Garner TP, Lopez A et al. (2017) Direct activation of BAX by BTSA1 overcomes apoptosis resistance in acute myeloid leukemia. Cancer Cell 32(4):490–505

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Robles AI, Harris CC (2017) Integration of multiple “OMIC” biomarkers: a precision medicine strategy for lung cancer. Lung Cancer 107:50–58

    Article  PubMed  Google Scholar 

  • Shi H, Bi H, Sun X et al. (2018) Antitumor effects of tubeimoside-1 in NCI-H1299 cells are mediated by microRNA-126-5p-induced inactivation of VEGF-A/VEGFR-2/ERK signaling pathway. Mol Med Rep 17(3):4327–4336

    CAS  PubMed  PubMed Central  Google Scholar 

  • Son S, Ko SK, Jang M et al. (2017) Polyketides and anthranilic acid possessing 6-deoxy-α-l-talopyranose from a Streptomyces species. J Nat Prod 80(5):1378–1386

    Article  CAS  PubMed  Google Scholar 

  • Torre LA, Bray F, Siegel RL et al. (2015) Global cancer statistics, 2012. Cancer J Clin 65:87–108

    Article  Google Scholar 

  • Trédan O, Galmarini CM, Patel K, Tannock IF (2007) Drug resistance and the solid tumor microenvironment. J Natl Cancer Inst 99:1441–1454

    Article  PubMed  CAS  Google Scholar 

  • Wang CY, Bai XY, Wang CH (2014) Traditional Chinese medicine: a treasured natural resource of anticancer drug research and development. Am J Chin Med 42:543–559

    Article  CAS  PubMed  Google Scholar 

  • Wang M, Li Y, Shao M et al. (2014) Separation and phylogenetic analysis of actinomycetes with activity of against Candida albicans from Chishui danxia soil. J Zunyi Med Univ 37(4):404–408.

    Google Scholar 

  • Wang Y, Shao M, Yue C (2016) Research development of halogenated natural products derived microorganisms. J Zunyi Med Univ 39(4):435–440.

    Google Scholar 

  • Wei WT, Lin SZ, Liu DL, Wang ZH (2013) The distinct mechanisms of the antitumor activity of emodin in different types of cancer (Review). Oncol Rep 30(6):2555–2562

    Article  CAS  PubMed  Google Scholar 

  • Xu P, Cai X, Zhang W et al. (2016) Flavonoids of Rosa roxburghii Tratt exhibit radioprotection and anti-apoptosis properties via the Bcl-2(Ca2+)/Caspase-3/PARP-1 pathway. Apoptosis 21(10):1125–1143

    Article  CAS  PubMed  Google Scholar 

  • Yu P, Shi L, Song M, Meng Y (2017) Antitumor activity of paederosidic acid in human non-small cell lung cancer cells via inducing mitochondria-mediated apoptosis. Chem Biol Inter 269:33–40

    Article  CAS  Google Scholar 

  • Zarogoulidis P, Petanidis S, Kioseoglou E et al. (2015) MiR-205 and miR-218 expression is associated with carboplatin chemoresistance and regulation of apoptosis via Mcl-1 and Survivin in lung cancer cells. Cell Signal 27(8):1576–1588

    Article  CAS  PubMed  Google Scholar 

  • Zhou L, Wu F, Jin W et al. (2017) Theabrownin inhibits cell cycle progression and tumor growth of lung carcinoma through c-myc-related mechanism. Front Pharm 8:75

    Google Scholar 

  • Zhou R, Chen H, Chen J et al. (2018) Extract from Astragalus membranaceus inhibit breast cancer cells proliferation via PI3K/AKT/mTOR signaling pathway. BMC Complement Alter Med 18:83

    Article  CAS  Google Scholar 

  • Zhu X, Jiang H, Li J et al. (2016) Anticancer effects of Paris saponins by apoptosis and PI3K/AKT Pathway in gefitinib-resistant non-small cell lung cancer. Med Sci Monit 22:1435–1441

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

The Authors would like to thank Yun Liu for his assistance with flow cytometry and Sanhua Li for her technical assistance. Especially, thanks to Changwu Yue for providing test compound of zunyimycin C. This work was funded by the National Nature Science Foundation of China (Grant no. 31460006), the Science and Technology Foundation of Guizhou Province (no. (2013) 3013).

Authors’ contributions

Study design: YB. Data acquisition: WL. Data analysis and interpretation: YB, ZQ, and WL. Statistical analysis: WL. Manuscript writing: WL. Manuscript editing: YB, ZQ. Manuscript review: WL, JZ, WW, YB, and ZQ.

Author information

Authors and Affiliations

  1. Research Center for Medicine & Biology, Zunyi Medical University, Zunyi, 563000, Guizhou, China

    Wei Li, Jie Zheng & Yuxin Bao

  2. Guizhou Provincial College-based Key Lab for Tumor Prevention & Treatment with Distinctive Medicines, Zunyi Medical University, Zunyi, 563000, Guizhou, China

    Wenhong Wang

  3. Laboratory of Neuropharmacology, Fudan University School of Pharmacy, 201203, Shanghai, China

    Zhongming Qian

  4. Center of Analysis & Measurement, Zunyi Medical University, Zunyi, 563099, Guizhou, China

    Yuxin Bao

Authors
  1. Wei Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jie Zheng
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Wenhong Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Zhongming Qian
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Yuxin Bao
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Yuxin Bao.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Li, W., Zheng, J., Wang, W. et al. Zunyimycin C inhibits the proliferation of lung cancer cells by inducing apoptosis through an AKT-related mechanism. Med Chem Res 28, 1828–1837 (2019). https://doi.org/10.1007/s00044-019-02417-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00044-019-02417-2

Keywords

Search

Navigation