PDK1 Inhibitor GSK-470 Exhibits Potent Anticancer Activity in a Pheochromocytoma PC12 Cell Tumor Model via Akt/mTOR Pathway

Author(s): Xiaohua Zhang, Shan Zhong*

Journal Name: Anti-Cancer Agents in Medicinal Chemistry
(Formerly Current Medicinal Chemistry - Anti-Cancer Agents)

Volume 20 , Issue 7 , 2020

Become EABM
Become Reviewer
Call for Editor

Graphical Abstract:


Background: Phosphoinositide-Dependent Kinase 1 (PDK1) is now widely studied in malignant solid tumors. Researchers have previously revealed that targeting PDK1 is thought of as a promising anticancer treatment strategy. The aim of this study was designed to evaluate the anticancer activity of GSK-470, a novel and highly specific inhibitor of PDK1, in Pheochromocytoma (PCC) tumor model.

Methods: PC12 cells were xenografted into nude mice to build PCC tumor model. Animals were treated with GSK-470 vs vehicle. Mean tumor volume was calculated and compared across groups. TUNEL was used to detect apoptosis. The effects of PDK1 inhibitor GSK-470 on activation of the Akt signaling and its downstream Akt/mTOR pathway in xenotransplant tumor tissues were examined by western bolt.

Results: The mean tumor volume in GSK-470 group was significantly less than that in control group. TUNEL results found that cell apoptosis was markedly increased in GSK-470 group compared with the control group. The western bolt analysis showed that the phosphorylation of Akt at threonine 308 was significantly reduced in GSK-470 group. Also, GSK-470 strongly inhibited phosphorylation of mTOR on Ser2448, a marker for mTORC1 activity, as well as phosphorylation of p70S6K, best characterized targets of mTOR.

Conclusion: Our results showed that GSK-470 exhibited potent anticancer activity in PC12 tumor-bearing mice. Also, we found that this effect appeared to be mediated by the inhibition of the Akt/mTOR pathway. The present study once again provides new insights into the therapeutic effects of inhibiting PDK1 in the treatment of malignant PCC. Therefore, we propose that GSK-470 might be an effective therapeutic agent for the treatment of malignant PCC.

Keywords: Pheochromocytoma, PDK1, GSK2334470, Akt, mTOR, anticancer.

Corssmit, E.P.M.; Snel, M.; Kapiteijn, E. Malignant pheochromocytoma and paraganglioma: management options. Curr. Opin. Oncol., 2020, 32(1), 20-26.
[http://dx.doi.org/10.1097/CCO.0000000000000589] [PMID: 31599769]
Hamidi, O.; Young, W.F., Jr; Iñiguez-Ariza, N.M.; Kittah, N.E.; Gruber, L.; Bancos, C.; Tamhane, S.; Bancos, I. Malignant pheochromocytoma and paraganglioma: 272 patients over 55 years. J. Clin. Endocrinol. Metab., 2017, 102(9), 3296-3305.
[http://dx.doi.org/10.1210/jc.2017-00992] [PMID: 28605453]
Lenders, J.W.M.; Eisenhofer, G. Update on modern management of pheochromocytoma and paraganglioma. Endocrinol. Metab. (Seoul), 2017, 32(2), 152-161.
[http://dx.doi.org/10.3803/EnM.2017.32.2.152] [PMID: 28685506]
Roman-Gonzalez, A.; Jimenez, C.; Fraenkel, M.; Gross, D.J.; Grossman, A.B.; Roman-Gonzalez, A.; Jimenez, C. Malignant pheochromocytoma-paraganglioma: pathogenesis, TNM staging, and current clinical trials. Curr. Opin. Endocrinol. Diabetes Obes., 2017, 24(3), 174-183.
[http://dx.doi.org/10.1097/MED.0000000000000330] [PMID: 28234804]
Jimenez, C. Treatment for patients with malignant pheochromocytomas and paragangliomas: A perspective from the hallmarks of cancer. Front. Endocrinol. (Lausanne), 2018, 9, 277.
[http://dx.doi.org/10.3389/fendo.2018.00277] [PMID: 29892268]
Jimenez, C.; Rohren, E.; Habra, M.A.; Rich, T.; Jimenez, P.; Ayala-Ramirez, M.; Baudin, E. Current and future treatments for malignant pheochromocytoma and sympathetic paraganglioma. Curr. Oncol. Rep., 2013, 15(4), 356-371.
[http://dx.doi.org/10.1007/s11912-013-0320-x] [PMID: 23674235]
Parenti, G.; Zampetti, B.; Rapizzi, E.; Ercolino, T.; Giachè, V.; Mannelli, M. Updated and new perspectives on diagnosis, prognosis, and therapy of malignant pheochromocytoma/paraganglioma. J. Oncol., 2012, 2012, 872713
[http://dx.doi.org/10.1155/2012/872713] [PMID: 22851969]
Jimenez, C.; Erwin, W.; Chasen, B. Targeted radionuclide therapy for patients with metastatic pheochromocytoma and paraganglioma: From low-specific-activity to high-specific-activity iodine-131 metaiodobenzylguanidine. Cancers (Basel), 2019, 11(7)E1018
[http://dx.doi.org/10.3390/cancers11071018] [PMID: 31330766]
Niemeijer, N.D.; Alblas, G.; van Hulsteijn, L.T.; Dekkers, O.M.; Corssmit, E.P. Chemotherapy with cyclophosphamide, vincristine and dacarbazine for malignant paraganglioma and pheochromocytoma: systematic review and meta-analysis. Clin. Endocrinol. (Oxf.), 2014, 81(5), 642-651.
[http://dx.doi.org/10.1111/cen.12542] [PMID: 25041164]
Jasim, S.; Suman, V.J.; Jimenez, C.; Harris, P.; Sideras, K.; Burton, J.K.; Worden, F.P.; Auchus, R.J.; Bible, K.C. Phase II trial of pazopanib in advanced/progressive malignant pheochromocytoma and paraganglioma. Endocrine, 2017, 57(2), 220-225.
[http://dx.doi.org/10.1007/s12020-017-1359-5] [PMID: 28685225]
Breen, W.; Bancos, I.; Young, W.F., Jr; Bible, K.C.; Laack, N.N.; Foote, R.L.; Hallemeier, C.L. External beam radiation therapy for advanced/unresectable malignant paraganglioma and pheochromocytoma. Adv. Radiat. Oncol., 2017, 3(1), 25-29.
[http://dx.doi.org/10.1016/j.adro.2017.11.002] [PMID: 29556576]
Kotecka-Blicharz, A.; Hasse-Lazar, K.; Handkiewicz-Junak, D.; Gawlik, T.; Pawlaczek, A.; Oczko-Wojciechowska, M.; Michalik, B.; Szpak-Ulczok, S.; Krajewska, J.; Jurecka-Lubieniecka, B.; Jarząb, B. 131-I MIBG therapy of malignant pheochromocytoma and paraganglioma tumours - a single-centre study. Endokrynol. Pol., 2018, 69(3), 246-251.
[http://dx.doi.org/10.5603/EP.a2018.0024] [PMID: 29645065]
Toledo, R.; Jimenez, C. Recent advances in the management of malignant pheochromocytoma and paraganglioma: focus on tyrosine kinase and hypoxia-inducible factor inhibitors. F1000 Res., 2018, 30, 7.
Jing, P.; Zhou, S.; Xu, P.; Cui, P.; Liu, X.; Liu, X.; Liu, X.; Wang, H.; Xu, W. PDK1 promotes metastasis by inducing epithelial-mesenchymal transition in hypopharyngeal carcinoma via the Notch1 signaling pathway. Exp. Cell Res., 2020, 386(2), 111746
[http://dx.doi.org/10.1016/j.yexcr.2019.111746] [PMID: 31778670]
Wang, Y.; Fu, L.; Cui, M.; Wang, Y.; Xu, Y.; Li, M. Amino acid transporter SLC38A3 promotes metastasis of non-small cell lung cancer cells by activating PDK1. Cancer Lett., 2017, 393, 8-15.
Emmanouilidi, A.; Falasca, M. Targeting PDK1 for chemosensitization of cancer cells. Cancers (Basel), 2017, 9(10), E140
[http://dx.doi.org/10.3390/cancers9100140] [PMID: 29064423]
Liu, T.; Yin, H. PDK1 promotes tumor cell proliferation and migration by enhancing the Warburg effect in non-small cell lung cancer. Oncol. Rep., 2017, 37(1), 193-200.
[http://dx.doi.org/10.3892/or.2016.5253] [PMID: 27878287]
Daniele, S.; Sestito, S.; Pietrobono, D.; Giacomelli, C.; Chiellini, G.; Di Maio, D.; Marinelli, L.; Novellino, E.; Martini, C.; Rapposelli, S. Dual inhibition of PDK1 and aurora kinase A: An effective strategy to induce differentiation and apoptosis of human glioblastoma multiforme stem cells. ACS Chem. Neurosci., 2017, 8(1), 100-114.
[http://dx.doi.org/10.1021/acschemneuro.6b00251] [PMID: 27797168]
Raimondi, C.; Calleja, V.; Ferro, R.; Fantin, A.; Riley, A.M.; Potter, B.V.; Brennan, C.H.; Maffucci, T.; Larijani, B.; Falasca, M. A small molecule inhibitor of PDK1/PLCγ1 interaction blocks breast and melanoma cancer cell invasion. Sci. Rep., 2016, 6, 26142.
[http://dx.doi.org/10.1038/srep26142] [PMID: 27199173]
Zhang, X.; Yu, Z. Expression of PDK1 in malignant pheochromocytoma as a new promising potential therapeutic target. Clin. Transl. Oncol., 2019, 21(10), 1312-1318.
[http://dx.doi.org/10.1007/s12094-019-02055-5] [PMID: 30759304]
Yang, C.; Huang, X.; Liu, H.; Xiao, F.; Wei, J.; You, L.; Qian, W. PDK1 inhibitor GSK2334470 exerts antitumor activity in multiple myeloma and forms a novel multitargeted combination with dual mTORC1/C2 inhibitor PP242. Oncotarget, 2017, 8(24), 39185-39197.
[http://dx.doi.org/10.18632/oncotarget.16642] [PMID: 28402933]
Zhang, J.; Yang, C.; Zhou, F.; Chen, X. PDK1 inhibitor GSK2334470 synergizes with proteasome inhibitor MG‑132 in multiple myeloma cells by inhibiting full AKT activity and increasing nuclear accumulation of the PTEN protein. Oncol. Rep., 2018, 39(6), 2951-2959.
[http://dx.doi.org/10.3892/or.2018.6369] [PMID: 29658600]
Wang, F.; Shan, S.; Huo, Y.; Xie, Z.; Fang, Y.; Qi, Z.; Chen, F.; Li, Y.; Sun, B. MiR-155-5p inhibits PDK1 and promotes autophagy via the mTOR pathway in cervical cancer. Int. J. Biochem. Cell Biol., 2018, 99, 91-99.
[http://dx.doi.org/10.1016/j.biocel.2018.04.005] [PMID: 29627439]
Gagliardi, P.A.; Puliafito, A.; Primo, L. PDK1: At the crossroad of cancer signaling pathways. Semin. Cancer Biol., 2018, 48, 27-35.
[http://dx.doi.org/10.1016/j.semcancer.2017.04.014] [PMID: 28473254]
Wada, M.; Horinaka, M.; Yasuda, S.; Masuzawa, M.; Sakai, T.; Katoh, N. PDK1 is a potential therapeutic target against angiosarcoma cells. J. Dermatol. Sci., 2015, 78(1), 44-50.
[http://dx.doi.org/10.1016/j.jdermsci.2015.01.015] [PMID: 25726712]
Gagliardi, P.A.; di Blasio, L.; Primo, L. PDK1: A signaling hub for cell migration and tumor invasion. Biochim. Biophys. Acta, 2015, 1856(2), 178-188.
[PMID: 26238471]
Raimondi, C.; Falasca, M. Targeting PDK1 in cancer. Curr. Med. Chem., 2011, 18(18), 2763-2769.
[http://dx.doi.org/10.2174/092986711796011238] [PMID: 21568903]
Keane, N.A.; Glavey, S.V.; Krawczyk, J.; O’Dwyer, M. AKT as a therapeutic target in multiple myeloma. Expert Opin. Ther. Targets, 2014, 18(8), 897-915.
[http://dx.doi.org/10.1517/14728222.2014.924507] [PMID: 24905897]
Sarbassov, D.D.; Guertin, D.A.; Ali, S.M.; Sabatini, D.M. Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex. Science, 2005, 307(5712), 1098-1101.
[http://dx.doi.org/10.1126/science.1106148] [PMID: 15718470]
Coant, N.; García-Barros, M.; Zhang, Q.; Obeid, L.M.; Hannun, Y.A. AKT as a key target for growth promoting functions of neutral ceramidase in colon cancer cells. Oncogene, 2018, 37(28), 3852-3863.
[http://dx.doi.org/10.1038/s41388-018-0236-x] [PMID: 29662189]
Su, A.R.; Qiu, M.; Li, Y.L.; Xu, W.T.; Song, S.W.; Wang, X.H.; Song, H.Y.; Zheng, N.; Wu, Z.W. BX-795 inhibits HSV-1 and HSV-2 replication by blocking the JNK/p38 pathways without interfering with PDK1 activity in host cells. Acta Pharmacol. Sin., 2017, 38(3), 402-414.
[http://dx.doi.org/10.1038/aps.2016.160] [PMID: 28112176]
Feldman, R.I.; Wu, J.M.; Polokoff, M.A.; Kochanny, M.J.; Dinter, H.; Zhu, D.; Biroc, S.L.; Alicke, B.; Bryant, J.; Yuan, S.; Buckman, B.O.; Lentz, D.; Ferrer, M.; Whitlow, M.; Adler, M.; Finster, S.; Chang, Z.; Arnaiz, D.O. Novel small molecule inhibitors of 3-phosphoinositide-dependent kinase-1. J. Biol. Chem., 2005, 280(20), 19867-19874.
[http://dx.doi.org/10.1074/jbc.M501367200] [PMID: 15772071]
Peifer, C.; Alessi, D.R. Small-molecule inhibitors of PDK1. ChemMedChem, 2008, 3(12), 1810-1838.
[http://dx.doi.org/10.1002/cmdc.200800195] [PMID: 18972468]
Sestito, S.; Rapposelli, S. A patent update on PDK1 inhibitors (2015-present). Expert Opin. Ther. Pat., 2015, 29(4), 271-282.
Najafov, A.; Sommer, E.M.; Axten, J.M.; Deyoung, M.P.; Alessi, D.R. Characterization of GSK2334470, a novel and highly specific inhibitor of PDK1. Biochem. J., 2011, 433(2), 357-369.
[http://dx.doi.org/10.1042/BJ20101732] [PMID: 21087210]
Knight, Z.A. For a PDK1 inhibitor, the substrate matters. Biochem. J., 2011, 433(2), e1-e2.
[http://dx.doi.org/10.1042/BJ20102038] [PMID: 21175429]

Rights & PermissionsPrintExport Cite as

Article Details

Year: 2020
Published on: 02 July, 2020
Page: [828 - 833]
Pages: 6
DOI: 10.2174/1871520620666200318100701
Price: $65

Article Metrics

PDF: 28