UNBS5162 inhibits proliferation of human melanoma cells by inducing apoptosis via the PI3K/Akt pathway

Shi,Xueli; Yang,Liu; Xie,Jun; Zhao,Yumei; Cong,Junzi; Li,Zhiping; Li,Haiyan; Cheng,Xianzhi; Fan,Jinghui

doi:10.3892/mmr.2018.9321

UNBS5162 inhibits proliferation of human melanoma cells by inducing apoptosis via the PI3K/Akt pathway

Authors:
- Xueli Shi
- Liu Yang
- Jun Xie
- Yumei Zhao
- Junzi Cong
- Zhiping Li
- Haiyan Li
- Xianzhi Cheng
- Jinghui Fan
View Affiliations

Affiliations: Department of Pharmacy, Hongqi Hospital Affiliated to Mudanjiang Medical University, Mudanjiang, Heilongjiang 157011, P.R. China, Department of Central Sterile Supply, Hongqi Hospital Affiliated to Mudanjiang Medical University, Mudanjiang, Heilongjiang 157011, P.R. China, Department of Nephrology, Hongqi Hospital Affiliated to Mudanjiang Medical University, Mudanjiang, Heilongjiang 157011, P.R. China
Published online on: July 25, 2018 https://doi.org/10.3892/mmr.2018.9321
Pages: 3382-3388

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

UNBS5162, a novel naphthalimide, is generated by UNBS3157 hydrolysis in physiological saline. In the present study, the effects of UNBS5162 on M14 human melanoma cells were evaluated by Cell Counting Kit‑8 and transwell assays, as well as western blotting. The underlying mechanism of apoptosis induced by UNBS5162 was investigated. The results demonstrated that proliferation of UNBS5162‑treated M14 melanoma cells was markedly inhibited in a time‑dependent manner. The flow cytometry results indicated a markedly increased apoptosis rate in the experimental group compared with in the control group (23.8±0.4 vs. 7.62±0.5%). Microscopy analysis revealed that the invasive and migratory abilities of UNBS5162‑treated M14 cells were markedly suppressed. Furthermore, UNBS5162 treatment led to decreased expression of the anti‑apoptotic protein B‑cell lymphoma 2, but increased expression of the pro‑apoptotic proteins Bcl‑2‑associated X protein and caspase‑3. In addition, the expression of several key proteins involved in the phosphatidylinositol‑4,5‑bisphosphate 3‑kinase/protein kinase B/mammalian target of rapamycin (PI3K/Akt/mTOR) signaling pathway was altered in M14 cells treated with UNBS5162. Based on these results, it may be hypothesized that UNBS5162 suppresses the proliferation of M14 cells by inducing apoptosis via inhibition of key proteins in the PI3K/Akt/mTOR signaling pathway.

View Figures

View References

1	Trinh VA: Current management of metastatic melanoma. Am J Health Syst Pharm. 65 Suppl 9:S3–S8. 2008. View Article : Google Scholar : PubMed/NCBI
2	Mete M, Sirakov NM, Griffin J and Menter A: A novel classification system for dysplastic nevus and malignant melanomaProceedings of the IEEE International Conference on Image Processing. Phoenix, AZ: pp. 3414–3418. 2016
3	Cho E, Rosner BA and Colditz GA: Risk factors for melanoma by body site. Cancer Epidemiol Biomarkers Prev. 14:1241–1244. 2005. View Article : Google Scholar : PubMed/NCBI
4	Trautmann F, Meier F, Seidler A and Schmitt J: Effects of the German skin cancer screening programme on melanoma incidence and indicators of disease severity. Br J Dermatol. 175:912–919. 2016. View Article : Google Scholar : PubMed/NCBI
5	Whiteman DC, Green AC and Olsen CM: The Growing Burden of Invasive Melanoma: Projections of Incidence Rates and Numbers of New Cases in Six Susceptible Populations through 2031. J Invest Dermatol. 136:1161–1171. 2016. View Article : Google Scholar : PubMed/NCBI
6	Ingrassia L, Lefranc F, Kiss R and Mijatovic T: Naphthalimides and azonafides as promising anti-cancer agents. Curr Med Chem. 16:1192–1213. 2009. View Article : Google Scholar : PubMed/NCBI
7	Ralhan R and Kaur J: Alkylating agents and cancer therapy. Expert Opin Ther Pat. 17:1061–1075. 2007. View Article : Google Scholar
8	Xie L, Cui J, Qian X, Xu Y, Liu J and Xu R: 5-Non-amino aromatic substituted naphthalimides as potential antitumor agents: Synthesis via Suzuki reaction, antiproliferative activity, and DNA-binding behavior. Bioorg Med Chem. 19:961–967. 2011. View Article : Google Scholar : PubMed/NCBI
9	Zhu H, Huang M, Yang F, Chen Y, Miao ZH, Qian XH, Xu YF, Qin YX, Luo HB, Shen X, et al: R16, a novel amonafide analogue, induces apoptosis and G2-M arrest via poisoning topoisomerase II. Mol Cancer Ther. 6:484–495. 2007. View Article : Google Scholar : PubMed/NCBI
10	Antonini I, Volpini R, Dal Ben D, Lambertucci C and Cristalli G: Design, synthesis, and biological evaluation of new mitonafide derivatives as potential antitumor drugs. Bioorg Med Chem. 16:8440–8446. 2008. View Article : Google Scholar : PubMed/NCBI
11	Braña MF, Cacho M, García MA, de Pascual-Teresa B, Ramos A, Domínguez MT, Pozuelo JM, Abradelo C, Rey-Stolle MF, Yuste M, et al: New analogues of amonafide and elinafide, containing aromatic heterocycles: Synthesis, antitumor activity, molecular modeling, and DNA binding properties. J Med Chem. 47:1391–1399. 2004. View Article : Google Scholar : PubMed/NCBI
12	Dumont P, Ribaucour F, Quaquebeke EV, Darro F and Kiss R: UNBS3157, a new amonafide derivative with improved in vivo efficacy and decreased toxicity. Cancer Res. 66:11052006.PubMed/NCBI
13	Van Quaquebeke E, Mahieu T, Dumont P, Dewelle J, Ribaucour F, Simon G, Sauvage S, Gaussin JF, Tuti J, El Yazidi M, et al: 2,2,2-Trichloro-N-({2-[2-(dimethylamino)ethyl]-1,3-dioxo-2,3-dihydro-1H-benzo[de]isoquinolin-5-yl}carbamoyl)acetamide (UNBS3157), a novel nonhematotoxic naphthalimide derivative with potent antitumor activity. J Med Chem. 50:4122–4134. 2007. View Article : Google Scholar : PubMed/NCBI
14	Seliga R, Pilatova M, Sarissky M, Viglasky V, Walko M and Mojzis J: Novel naphthalimide polyamine derivatives as potential antitumor agents. Mol Biol Rep. 40:4129–4137. 2013. View Article : Google Scholar : PubMed/NCBI
15	Mahieu T, Mijatovic T, Quaquebeke EV, Lefranc F, Vynckt FV, Darro F and Kiss R: UNBS5162 is a novel naphthalimide derivative that induces autophagy and senescence in human prostate cancer cells. Mol Cancer Ther. 6:3373S2007.
16	Mijatovic T, Mahieu T, Bruyère C, De Nève N, Dewelle J, Simon G, Dehoux MJM, van der Aar E, Haibe-Kains B, Bontempi G, et al: UNBS5162, a novel naphthalimide that decreases CXCL chemokine expression in experimental prostate cancers. Neoplasia. 10:573–586. 2008. View Article : Google Scholar : PubMed/NCBI
17	Babchia N, Calipel A, Mouriaux F, Faussat AM and Mascarelli F: The PI3K/Akt and mTOR/P70S6K signaling pathways in human uveal melanoma cells: Interaction with B-Raf/ERK. Invest Ophthalmol Vis Sci. 51:421–429. 2010. View Article : Google Scholar : PubMed/NCBI
18	Wang B, Shen J and Wang J: UNBS5162 inhibits proliferation of human retinoblastoma cells by promoting cell apoptosis. OncoTargets Ther. 10:5303–5309. 2017. View Article : Google Scholar
19	Kiliçkan L, Gonca S, Dalçik C, Dalçik H, Solak M, Bayindir O, Süzer K, Omay O and Calikan E: General anesthesia with thoracic epidural anesthesia in the cardiopulmonary bypass surgery reduces apoptosis by upregulating antiapoptotic protein Bcl-2. J Cardiovasc Surg (Torino). 47:315–322. 2006.PubMed/NCBI
20	Siddiqui WA, Ahad A and Ahsan H: The mystery of BCL2 family: Bcl-2 proteins and apoptosis: an update. Arch Toxicol. 89:289–317. 2015. View Article : Google Scholar : PubMed/NCBI
21	Wojtuszkiewicz A, Schuurhuis GJ, Kessler FL, Piersma SR, Knol JC, Pham TV, Jansen G, Musters RJ, van Meerloo J, Assaraf YG, et al: Exosomes Secreted by Apoptosis-Resistant Acute Myeloid Leukemia (AML) Blasts Harbor Regulatory Network Proteins Potentially Involved in Antagonism of Apoptosis. Mol Cell Proteomics. 15:1281–1298. 2016. View Article : Google Scholar : PubMed/NCBI
22	Huang L, Han J, Ben-Hail D, He L, Li B, Chen Z, Wang Y, Yang Y, Liu L, Zhu Y, et al: A New Fungal Diterpene Induces VDAC1-dependent Apoptosis in Bax/Bak-deficient Cells. J Biol Chem. 290:23563–23578. 2015. View Article : Google Scholar : PubMed/NCBI
23	Singh L, Pushker N, Saini N, Sen S, Sharma A, Bakhshi S, Chawla B and Kashyap S: Expression of pro-apoptotic Bax and anti-apoptotic Bcl-2 proteins in human retinoblastoma. Clin Experiment Ophthalmol. 43:259–267. 2015. View Article : Google Scholar : PubMed/NCBI
24	Zhu L, Han MB, Gao Y, Wang H, Dai L, Wen Y and Na LX: Curcumin triggers apoptosis via upregulation of Bax/Bcl-2 ratio and caspase activation in SW872 human adipocytes. Mol Med Rep. 12:1151–1156. 2015. View Article : Google Scholar : PubMed/NCBI
25	Zhou S, Wang Y and Zhu JJ: Simultaneous Detection of Tumor Cell Apoptosis Regulators Bcl-2 and Bax through a Dual-Signal-Marked Electrochemical Immunosensor. ACS Appl Mater Interfaces. 8:7674–7682. 2016. View Article : Google Scholar : PubMed/NCBI
26	Jiang H, Liu J, Gao J, Meng M, Qin X and Wang T: Up-regulations of Bax and caspase-3 and down-regulation of Bcl-2 after Xinfeng capsule treatment in adjuvant-induced arthritis rats. Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi. 32:457–461. 2016.(In Chinese). PubMed/NCBI
27	Wang D, Chen J, Chen H, Duan Z, Xu Q, Wei M, Wang L and Zhong M: Leptin regulates proliferation and apoptosis of colorectal carcinoma through PI3K/Akt/mTOR signalling pathway. J Biosci. 37:91–101. 2012. View Article : Google Scholar : PubMed/NCBI
28	Kang S, Dong SM, Kim BR, Park MS, Trink B, Byun HJ and Rho SB: Thioridazine induces apoptosis by targeting the PI3K/Akt/mTOR pathway in cervical and endometrial cancer cells. Apoptosis. 17:989–997. 2012. View Article : Google Scholar : PubMed/NCBI
29	Sun CH, Chang YH and Pan CC: Activation of the PI3K/Akt/mTOR pathway correlates with tumour progression and reduced survival in patients with urothelial carcinoma of the urinary bladder. Histopathology. 58:1054–1063. 2011. View Article : Google Scholar : PubMed/NCBI
30	Jiang Z, Liu Y and Wang C: Oncogenic NanogP8 expression regulates cell proliferation and migration through the Akt/mTOR signaling pathway in human gastric cancer - SGC-7901cell line. OncoTargets Ther. 9:4859–4866. 2016. View Article : Google Scholar
31	Leleu X, Coiteux V, Corm S, Robu D, Dupire S, Moreau AS, Gay J, Berthon C, Pascal L, Cliquenois E, et al: The AKT signaling pathway is the key regulator of cell survival and homing in Waldenstrom macroglobulinemia. Hématologie. 14:14–17. 2008.
32	Yang H, Zhou J, Mi J, Ma K, Fan Y, Ning J, Wang C, Wei X, Zhao H and Li E: HOXD10 acts as a tumor-suppressive factor via inhibition of the RHOC/AKT/MAPK pathway in human cholangiocellular carcinoma. Oncol Rep. 34:1681–1691. 2015. View Article : Google Scholar : PubMed/NCBI
33	Asnaghi L, Bruno P, Priulla M and Nicolin A: mTOR: A protein kinase switching between life and death. Pharmacol Res. 50:545–549. 2004. View Article : Google Scholar : PubMed/NCBI
34	Yu JS and Cui W: Proliferation, survival and metabolism: The role of PI3K/AKT/mTOR signalling in pluripotency and cell fate determination. Development. 143:3050–3060. 2016. View Article : Google Scholar : PubMed/NCBI
35	Liu YD, Zheng QX, Wu HB, Guo XD, Li JF and Hao SF: The effects of rapamycin on expression ratio of Bax/Bcl-2 and the expression of activated caspase-3 in different types of tumor cells. Tumor. 33(2)2013.