Anti‑proliferative effect of cardamonin on mTOR inhibitor‑resistant cancer cells

Niu,Peiguang; Li,Jinsui; Chen,Huajiao; Zhu,Yanting; Zhou,Jintuo; Shi,Daohua

doi:10.3892/mmr.2019.10898

Anti‑proliferative effect of cardamonin on mTOR inhibitor‑resistant cancer cells

Authors:
- Peiguang Niu
- Jinsui Li
- Huajiao Chen
- Yanting Zhu
- Jintuo Zhou
- Daohua Shi
View Affiliations

Affiliations: Department of Pharmacy, Fujian Provincial Maternity and Children's Hospital, Affiliated Hospital of Fujian Medical University, Fuzhou, Fujian 350001, P.R. China
Published online on: December 20, 2019 https://doi.org/10.3892/mmr.2019.10898
Pages: 1399-1407

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

A number of mammalian target of rapamycin (mTOR) inhibitors have been approved for the treatment of certain types of cancer or are currently undergoing clinical trials. However, mTOR targeted therapy exerts selective pressure on tumour cells, which leads to the preferential growth of resistant subpopulations. There are two classes of mTOR inhibitors: i) The rapalogs, such as rapamycin, which bind to the 12‑kDa FK506‑binding protein/rapamycin‑binding domain of mTOR; and ii) the ATP‑competitive inhibitors, such as AZD8055, which block the mTOR kinase domain. Cardamonin inhibits mTOR by decreasing the expression of regulatory‑associated protein of mTOR (Raptor), a mechanism of action which differs from the currently available mTOR inhibitors. The present study investigated the inhibitory effects of cardamonin on mTOR inhibitor‑resistant cancer cells. HeLa cervical cancer cells and MCF‑7 breast cancer cells were exposed to high concentrations of mTOR inhibitors, until resistant clones emerged. Cytotoxicity was measured using the MTT and colony forming assays. The inhibitory effect of cardamonin on mTOR signalling was assessed by western blotting. The resistant cells were less sensitive to mTOR inhibitors compared with the parental cells. Consistent with the anti‑proliferation effect, rapamycin and AZD8055 had no effect on the phosphorylation of rapamycin‑sensitive sites on ribosomal protein S6 kinase B1 (S6K1) and AZD8055‑sensitive sites on protein kinase B and eukaryotic translation initiation factor 4E binding protein 1 (Thr 37/46), respectively, in rapamycin‑ and AZD8055‑resistant cells. Cardamonin inhibited cell proliferation and decreased the phosphorylation of mTOR and S6K1, as well as the protein level of raptor, in the mTOR inhibitor‑resistant cells. Therefore, cardamonin may serve as a therapeutic agent for patients with cervical and breast cancer resistant to mTOR inhibitors.

View Figures

View References

1	Saxton RA and Sabatini DM: mTOR signaling in growth, metabolism, and disease. Cell. 169:361–371. 2017. View Article : Google Scholar : PubMed/NCBI
2	Mossmann D, Park S and Hall MN: mTOR signalling and cellular metabolism are mutual determinants in cancer. Nat Rev Cancer. 18:744–757. 2018. View Article : Google Scholar : PubMed/NCBI
3	Sabatini DM: Twenty-five years of mTOR: Uncovering the link from nutrients to growth. Proc Natl Acad Sci USA. 114:11818–11825. 2017. View Article : Google Scholar : PubMed/NCBI
4	Jordan NJ, Dutkowski CM, Barrow D, Mottram HJ, Hutcheson IR, Nicholson RI, Guichard SM and Gee JM: Impact of dual mTORC1/2 mTOR kinase inhibitor AZD8055 on acquired endocrine resistance in breast cancer in vitro. Breast Cancer Res. 16:R122014. View Article : Google Scholar : PubMed/NCBI
5	Barra F, Evangelisti G, Ferro Desideri L, Di Domenico S, Ferraioli D, Vellone VG, De Cian F and Ferrero S: Investigational PI3K/AKT/mTOR inhibitors in development for endometrial cancer. Expert Opin Investig Drugs. 28:131–142. 2019. View Article : Google Scholar : PubMed/NCBI
6	Li J, Kim SG and Blenis J: Rapamycin: One drug, many effects. Cell Metab. 19:373–379. 2014. View Article : Google Scholar : PubMed/NCBI
7	Oshiro N, Yoshino K, Hidayat S, Tokunaga C, Hara K, Eguchi S, Avruch J and Yonezawa K: Dissociation of raptor from mTOR is a mechanism of rapamycin-induced inhibition of mTOR function. Genes Cells. 9:359–366. 2004. View Article : Google Scholar : PubMed/NCBI
8	Yip CK, Murata K, Walz T, Sabatini DM and Kang SA: Structure of the human mTOR complex I and its implications for rapamycin inhibition. Mol Cell. 38:768–774. 2010. View Article : Google Scholar : PubMed/NCBI
9	Meng LH and Zheng XF: Toward rapamycin analog (rapalog)-based precision cancer therapy. Acta Pharmacol Sin. 36:1163–1169. 2015. View Article : Google Scholar : PubMed/NCBI
10	Owonikoko TK: Inhibitors of mTOR pathway for cancer therapy, moving on from rapalogs to TORKinibs. Cancer. 121:3390–3392. 2015. View Article : Google Scholar : PubMed/NCBI
11	Chiarini F, Evangelisti C, McCubrey JA and Martelli AM: Current treatment strategies for inhibiting mTOR in cancer. Trends Pharmacol Sci. 36:124–135. 2015. View Article : Google Scholar : PubMed/NCBI
12	Wagle N, Grabiner BC, Van Allen EM, Hodis E, Jacobus S, Supko JG, Stewart M, Choueiri TK, Gandhi L, Cleary JM, et al: Activating mTOR mutations in a patient with an extraordinary response on a phase I trial of everolimus and pazopanib. Cancer Discov. 4:546–553. 2014. View Article : Google Scholar : PubMed/NCBI
13	Schenone S, Brullo C, Musumeci F, Radi M and Botta M: ATP-competitive inhibitors of mTOR: An update. Curr Med Chem. 18:2995–3014. 2011. View Article : Google Scholar : PubMed/NCBI
14	English DP, Roque DM, Carrara L, Lopez S, Bellone S, Cocco E, Bortolomai I, Schwartz PE, Rutherford T and Santin AD: HER2/neu gene amplification determines the sensitivity of uterine serous carcinoma cell lines to AZD8055, a novel dual mTORC1/2 inhibitor. Gynecol Oncol. 131:753–758. 2013. View Article : Google Scholar : PubMed/NCBI
15	Zhang Y, Jia QA, Kadel D, Zhang XF and Zhang QB: Targeting mTORC1/2 complexes inhibit tumorigenesis and enhance sensitivity to 5-flourouracil (5-FU) in hepatocellular carcinoma: A preclinical study of mTORC1/2-targeted therapy in hepatocellular carcinoma (HCC). Med Sci Monit. 24:2735–2743. 2018. View Article : Google Scholar : PubMed/NCBI
16	Xu DQ, Toyoda H, Qi L, Morimoto M, Hanaki R, Iwamoto S, Komada Y and Hirayama M: Induction of MEK/ERK activity by AZD8055 confers acquired resistance in neuroblastoma. Biochem Biophys Res Commun. 499:425–432. 2018. View Article : Google Scholar : PubMed/NCBI
17	Rodrik-Outmezguine VS, Chandarlapaty S, Pagano NC, Poulikakos PI, Scaltriti M, Moskatel E, Baselga J, Guichard S and Rosen N: mTOR kinase inhibition causes feedback-dependent biphasic regulation of AKT signaling. Cancer Discov. 1:248–259. 2011. View Article : Google Scholar : PubMed/NCBI
18	Chen H, Shi D, Niu P, Zhu Y and Zhou J: Anti-inflammatory effects of cardamonin in ovarian cancer cells are mediated via mTOR suppression. Planta Med. 84:1183–1190. 2018. View Article : Google Scholar : PubMed/NCBI
19	Niu PG, Zhang YX, Shi DH, Liu Y, Chen YY and Deng J: Cardamonin inhibits metastasis of lewis lung carcinoma cells by decreasing mTOR activity. PLoS One. 10:e01277782015. View Article : Google Scholar : PubMed/NCBI
20	Tang Y, Fang Q, Shi D, Niu P, Chen Y and Deng J: mTOR inhibition of cardamonin on antiproliferation of A549 cells is involved in a FKBP12 independent fashion. Life Sci. 99:44–51. 2014. View Article : Google Scholar : PubMed/NCBI
21	Break MKB, Hossan MS, Khoo Y, Qazzaz ME, Al-Hayali MZK, Chow SC, Wiart C, Bradshaw TD, Collins H and Khoo TJ: Discovery of a highly active anticancer analogue of cardamonin that acts as an inducer of caspase-dependent apoptosis and modulator of the mTOR pathway. Fitoterapia. 125:161–173. 2018. View Article : Google Scholar : PubMed/NCBI
22	Zhou X, Zhou R, Li Q, Jie X, Hong J, Zong Y, Dong X, Zhang S, Li Z and Wu G: Cardamonin inhibits the proliferation and metastasis of non-small-cell lung cancer cells by suppressing the PI3K/Akt/mTOR pathway. Anticancer Drugs. 30:241–250. 2019. View Article : Google Scholar : PubMed/NCBI
23	Jin J, Qiu S, Wang P, Liang X, Huang F, Wu H, Zhang B, Zhang W, Tian X, Xu R, et al: Cardamonin inhibits breast cancer growth by repressing HIF-1α-dependent metabolic reprogramming. J Exp Clin Cancer Res. 38:3772019. View Article : Google Scholar : PubMed/NCBI
24	Shi D, Niu P, Heng X, Chen L, Zhu Y and Zhou J: Autophagy induced by cardamonin is associated with mTORC1 inhibition in SKOV3 cells. Pharmacol Rep. 70:908–916. 2018. View Article : Google Scholar
25	Shi D, Zhu Y, Niu P, Zhou J and Chen H: Raptor mediates the antiproliferation of cardamonin by mTORC1 inhibition in SKOV3 cells. Onco Targets Ther. 11:757–767. 2018. View Article : Google Scholar : PubMed/NCBI
26	You W, Wu Z, Ye F and Wu X: Cardamonin protects against adverse cardiac remodeling through mTORC1 inhibition in mice with myocardial infarction. Pharmazie. 73:508–512. 2018.PubMed/NCBI
27	Du L, Li X, Zhen L, Chen W, Mu L, Zhang Y and Song A: Everolimus inhibits breast cancer cell growth through PI3K/AKT/mTOR signaling pathway. Mol Med Rep. 17:7163–7169. 2018.PubMed/NCBI
28	Guerrero-Zotano A, Mayer IA and Arteaga CL: PI3K/AKT/mTOR: Role in breast cancer progression, drug resistance, and treatment. Cancer Metastasis Rev. 35:515–524. 2016. View Article : Google Scholar : PubMed/NCBI
29	Dey N, De P and Leyland-Jones B: PI3K-AKT-mTOR inhibitors in breast cancers: From tumor cell signaling to clinical trials. Pharmacol Ther. 175:91–106. 2017. View Article : Google Scholar : PubMed/NCBI
30	Tian T, Li X and Zhang J: mTOR signaling in cancer and mTOR inhibitors in solid tumor targeting therapy. Int J Mol Sci. 20(pii): E7552019. View Article : Google Scholar : PubMed/NCBI
31	Kapoor A and Figlin RA: Targeted inhibition of mammalian target of rapamycin for the treatment of advanced renal cell carcinoma. Cancer. 115:3618–3630. 2009. View Article : Google Scholar : PubMed/NCBI
32	Hudes G, Carducci M, Tomczak P, Dutcher J, Figlin R, Kapoor A, Staroslawska E, Sosman J, McDermott D, Bodrogi I, et al: Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma. N Engl J Med. 356:2271–2281. 2007. View Article : Google Scholar : PubMed/NCBI
33	Koh KX, Tan GH, Hui Low SH, Mohd Omar MF, Han MJ, Iacopetta B, Soo R, Beloueche-Babari M, Bhattacharya B and Soong R: Acquired resistance to PI3K/mTOR inhibition is associated with mitochondrial DNA mutation and glycolysis. Oncotarget. 8:110133–110144. 2017. View Article : Google Scholar : PubMed/NCBI
34	Hassan B, Akcakanat A, Sangai T, Evans KW, Adkins F, Eterovic AK, Zhao H, Chen K, Chen H, Do KA, et al: Catalytic mTOR inhibitors can overcome intrinsic and acquired resistance to allosteric mTOR inhibitors. Oncotarget. 5:8544–8557. 2014. View Article : Google Scholar : PubMed/NCBI
35	Rodrik-Outmezguine VS, Okaniwa M, Yao Z, Novotny CJ, McWhirter C, Banaji A, Won H, Wong W, Berger M, de Stanchina E, et al: Overcoming mTOR resistance mutations with a new-generation mTOR inhibitor. Nature. 534:272–276. 2016. View Article : Google Scholar : PubMed/NCBI
36	Santoni M, Pantano F, Amantini C, Nabissi M, Conti A, Burattini L, Zoccoli A, Berardi R, Santoni G, Tonini G, et al: Emerging strategies to overcome the resistance to current mTOR inhibitors in renal cell carcinoma. Biochim Biophys Acta. 1845:221–231. 2014.PubMed/NCBI
37	Weisman R and Choder M: The fission yeast TOR homolog, tor1+, is required for the response to starvation and other stresses via a conserved serine. J Biol Chem. 276:7027–7032. 2001. View Article : Google Scholar : PubMed/NCBI
38	Grabiner BC, Nardi V, Birsoy K, Possemato R, Shen K, Sinha S, Jordan A, Beck AH and Sabatini DM: A diverse array of cancer-associated MTOR mutations are hyperactivating and can predict rapamycin sensitivity. Cancer Discov. 4:554–563. 2014. View Article : Google Scholar : PubMed/NCBI
39	Wagle N, Grabiner BC, Van Allen EM, Amin-Mansour A, Taylor-Weiner A, Rosenberg M, Gray N, Barletta JA, Guo Y, Swanson SJ, et al: Response and acquired resistance to everolimus in anaplastic thyroid cancer. N Engl J Med. 371:1426–1433. 2014. View Article : Google Scholar : PubMed/NCBI
40	Earwaker P, Anderson C, Willenbrock F, Harris AL, Protheroe AS and Macaulay VM: RAPTOR up-regulation contributes to resistance of renal cancer cells to PI3K-mTOR inhibition. PLoS One. 13:e01918902018. View Article : Google Scholar : PubMed/NCBI
41	Mateo F, Arenas EJ, Aguilar H, Serra-Musach J, de Garibay GR, Boni J, Maicas M, Du S, Iorio F, Herranz-Ors C, et al: Stem cell-like transcriptional reprogramming mediates metastatic resistance to mTOR inhibition. Oncogene. 36:2737–2749. 2017. View Article : Google Scholar : PubMed/NCBI