Generic placeholder image

Anti-Cancer Agents in Medicinal Chemistry

Author(s): Alican Kusoglu*, Bakiye G. Bagca, Neslihan P.O. Ay, Guray Saydam and Cigir B. Avci

DOI: 10.2174/1871520620666200218105159

DownloadDownload PDF Flyer Cite As
Ruxolitinib Regulates the Autophagy Machinery in Multiple Myeloma Cells

Page: [2316 - 2323] Pages: 8

  • * (Excluding Mailing and Handling)

Abstract

Background: Ruxolitinib is a selective JAK1/2 inhibitor approved by the FDA for myelofibrosis in 2014 and nowadays, comprehensive investigations on the potential of the agent as a targeted therapy for haematological malignancies are on the rise. In multiple myeloma which is a cancer of plasma cells, the Interleukin- 6/JAK/STAT pathway is emerging as a therapeutic target since the overactivation of the pathway is associated with poor prognosis.

Objective: In this study, our purpose was to discover the potential anticancer effects of ruxolitinib in ARH-77 multiple myeloma cell line compared to NCI-BL 2171 human healthy B lymphocyte cell line.

Methods: Cytotoxic effects of ruxolitinib in ARH-77 and NCI-BL 2171 cells were determined via WST-1 assay. The autophagy mechanism induced by ruxolitinib measured by detecting autophagosome formation was investigated. Apoptotic effects of ruxolitinib were analyzed with Annexin V-FITC Detection Kit and flow cytometry. We performed RT-qPCR to demonstrate the expression changes of the genes in the IL-6/JAK/STAT pathway in ARH-77 and NCI-BL 2171 cells treated with ruxolitinib.

Results: We identified the IC50 values of ruxolitinib for ARH-77 and NCI-BL 2171 as 20.03 and 33.9μM at the 72nd hour, respectively. We showed that ruxolitinib induced autophagosome accumulation by 3.45 and 1.70 folds in ARH-77 and NCI-BL 2171 cells compared to the control group, respectively. Treatment with ruxolitinib decreased the expressions of IL-6, IL-18, JAK2, TYK2, and AKT genes, which play significant roles in MM pathogenesis.

Conclusion: All in all, ruxolitinib is a promising agent for the regulation of the IL-6/JAK/STAT pathway and interferes with the autophagy mechanism in MM.

Keywords: Ruxolitinib, multiple myeloma, autophagy, Interleukin-6, JAK, STAT.

Graphical Abstract

[1]
Siegel, R.L.; Miller, K.D.; Jemal, A. Cancer statistics, 2016. CA Cancer J. Clin., 2016, 66(1), 7-30.
[http://dx.doi.org/10.3322/caac.21332 ] [PMID: 26742998]
[2]
Kumar, S.K.; Rajkumar, V.; Kyle, R.A.; van Duin, M.; Sonneveld, P.; Mateos, M.V.; Gay, F.; Anderson, K.C. Multiple myeloma. Nat. Rev. Dis. Primers, 2017, 3, 17046.
[http://dx.doi.org/10.1038/nrdp.2017.46 ] [PMID: 28726797]
[3]
Kazandjian, D. Multiple myeloma epidemiology and survival: A unique malignancy. Semin. Oncol., 2016, 43(6), 676-681.
[http://dx.doi.org/10.1053/j.seminoncol.2016.11.004 ] [PMID: 28061985]
[4]
Eslick, R.; Talaulikar, D. Multiple myeloma: From diagnosis to treatment. Aust. Fam. Physician, 2013, 42(10), 684-688.https://doi.org/42(10):684-8
[PMID: 24130968]
[5]
Murray, M.Y.; Auger, M.J.; Bowles, K.M. Overcoming bortezomib resistance in multiple myeloma. Biochem. Soc. Trans., 2014, 42(4), 804-808.
[http://dx.doi.org/10.1042/BST20140126 ] [PMID: 25109961]
[6]
Leach, A.P. Apoptosis: Molecular mechanism for physiologic cell death. Clin. Lab. Sci., 1998, 11(6), 346-349.
[PMID: 10345500]
[7]
Oancea, M.; Mani, A.; Hussein, M.A.; Almasan, A. Apoptosis of multiple myeloma. Int. J. Hematol., 2004, 80(3), 224-231.
[http://dx.doi.org/10.1532/IJH97.04107 ] [PMID: 15540896]
[8]
Singh, S.S.; Vats, S.; Chia, A.Y-Q.; Tan, T.Z.; Deng, S.; Ong, M.S.; Arfuso, F.; Yap, C.T.; Goh, B.C.; Sethi, G. Dual role of autophagy in hallmarks of cancer. Oncogene, 2018, 37, 1142-1158.
[http://dx.doi.org/10.1038/s41388-017-0046-6] [PMID: 29255248]
[9]
Ameisen, J.C. On the origin, evolution, and nature of programmed cell death: A timeline of four billion years. Cell Death Differ., 2002, 9(4), 367-393.
[http://dx.doi.org/10.1038/sj.cdd.4400950 ] [PMID: 11965491]
[10]
Ojha, R.; Bhattacharyya, S.; Singh, S.K. Autophagy in cancer stem cells: A potential link between chemoresistance, recurrence, and metastasis. Biores. Open Access, 2015, 4(1), 97-108.
[11]
Mesa, R.A.; Yasothan, U.; Kirkpatrick, P. Ruxolitinib. Nat. Rev. Drug Discov., 2012, 11(2), 103-104.
[http://dx.doi.org/10.1038/nrd3652 ] [PMID: 22293561]
[12]
Rawlings, J.S.; Rosler, K.M.; Harrison, D.A. The JAK/STAT signaling pathway. J. Cell Sci., 2004, 117(Pt 8), 1281-1283.
[http://dx.doi.org/10.1242/jcs.00963 ] [PMID: 15020666]
[13]
Bousoik, E.; Montazeri Aliabadi, H. “Do We Know Jack” about JAK? A closer look at JAK/STAT signaling pathway. Front. Oncol., 2018, 8(July), 287.
[http://dx.doi.org/10.3389/fonc.2018.00287 ] [PMID: 30109213]
[14]
Civallero, M.; Cosenza, M.; Pozzi, S.; Sacchi, S. Ruxolitinib combined with vorinostat suppresses tumor growth and alters metabolic phenotype in hematological diseases. Oncotarget, 2017, 8(61), 103797-103814.
[http://dx.doi.org/10.18632/oncotarget.21951 ] [PMID: 29262601]
[15]
Johnson, D.E.; O’Keefe, R.A.; Grandis, J.R. Targeting the IL-6/JAK/STAT3 signalling axis in cancer. Nat. Rev. Clin. Oncol., 2018, 15(4), 234-248.
[http://dx.doi.org/10.1038/nrclinonc.2018.8 ] [PMID: 29405201]
[16]
Sansone, P.; Bromberg, J. Targeting the interleukin-6/Jak/stat pathway in human malignancies. J. Clin. Oncol., 2012, 30(9), 1005-1014.
[http://dx.doi.org/10.1200/JCO.2010.31.8907 ] [PMID: 22355058]
[17]
van de Donk, N.W.C.J.; Lokhorst, H.M.; Bloem, A.C. Growth factors and antiapoptotic signaling pathways in multiple myeloma. Leukemia, 2005, 19(12), 2177-2185.
[http://dx.doi.org/10.1038/sj.leu.2403970 ] [PMID: 16239913]
[18]
Brocke-Heidrich, K.; Kretzschmar, A.K.; Pfeifer, G.; Henze, C.; Löffler, D.; Koczan, D.; Thiesen, H.J.; Burger, R.; Gramatzki, M.; Horn, F. Interleukin-6-dependent gene expression profiles in multiple myeloma INA-6 cells reveal a Bcl-2 family-independent survival pathway closely associated with Stat3 activation. Blood, 2004, 103(1), 242-251.
[http://dx.doi.org/10.1182/blood-2003-04-1048 ] [PMID: 12969979]
[19]
Cyster, J.G. Homing of antibody secreting cells. Immunol. Rev., 2003, 194, 48-60.
[http://dx.doi.org/10.1034/j.1600-065X.2003.00041.x ] [PMID: 12846807]
[20]
Manier, S.; Kawano, Y.; Bianchi, G.; Roccaro, A.M.; Ghobrial, I.M. Cell autonomous and microenvironmental regulation of tumor progression in precursor states of multiple myeloma. Curr. Opin. Hematol., 2016, 23(4), 426-433.
[http://dx.doi.org/10.1097/MOH.0000000000000259 ] [PMID: 27101529]
[21]
Alexandrakis, M.G.; Passam, F.H.; Sfiridaki, K.; Moschandrea, J.; Pappa, C.; Liapi, D.; Petreli, E.; Roussou, P.; Kyriakou, D.S. Interleukin-18 in multiple myeloma patients: Serum levels in relation to response to treatment and survival. Leuk. Res., 2004, 28(3), 259-266.
[http://dx.doi.org/10.1016/S0145-2126(03)00261-3] [PMID: 14687621]
[22]
Nakamura, K.; Kassem, S.; Cleynen, A.; Chrétien, M.L.; Guillerey, C.; Putz, E.M.; Bald, T.; Förster, I.; Vuckovic, S.; Hill, G.R.; Masters, S.L.; Chesi, M.; Bergsagel, P.L.; Avet-Loiseau, H.; Martinet, L.; Smyth, M.J. Dysregulated IL-18 is a key driver of immunosuppression and a possible therapeutic target in the multiple myeloma microenvironment. Cancer Cell, 2018, 33(4), 634-648.
[http://dx.doi.org/10.1016/j.ccell.2018.02.007 ] [PMID: 29551594]
[23]
Schjesvold, F.H.; Haabeth, O.A.; Bogen, B.; Tveita, A. CSF1R-inhibition and reduction of macrophages delays multiple myeloma growth in a non-T-cell-dependent manner. Blood, 2014, 124(21), 5717.
[http://dx.doi.org/10.1182/blood.V124.21.5717.5717]
[24]
Yang, X.D.; Huang, P.; Wang, F.; Xu, Z.K. Expression of granulocyte colony-stimulating factor receptor in rectal cancer. World J. Gastroenterol., 2014, 20(4), 1074-1078.
[http://dx.doi.org/10.3748/wjg.v20.i4.1074 ] [PMID: 24574781]
[25]
Woo, H.H.; László, C.F.; Greco, S.; Chambers, S.K. Regulation of colony stimulating factor-1 expression and ovarian cancer cell behavior in vitro by miR-128 and miR-152. Mol. Cancer, 2012, 11, 58.
[http://dx.doi.org/10.1186/1476-4598-11-58] [PMID: 22909061]
[26]
Tavallai, M.; Booth, L.; Roberts, J.L.; Poklepovic, A.; Dent, P. Rationally repurposing ruxolitinib (Jakafi(®)) as a solid tumor therapeutic. Front. Oncol., 2016, 6, 142.
[http://dx.doi.org/10.3389/fonc.2016.00142 ] [PMID: 27379204]
[27]
Tu, Y.; Gardner, A.; Lichtenstein, A. The phosphatidylinositol 3-kinase/AKT kinase pathway in multiple myeloma plasma cells: Roles in cytokine-dependent survival and proliferative responses. Cancer Res., 2000, 60(23), 6763-6770.
[PMID: 11118064]
[28]
Hideshima, T.; Nakamura, N.; Chauhan, D.; Anderson, K.C. Biologic sequelae of interleukin-6 induced PI3-K/Akt signaling in multiple myeloma. Oncogene, 2001, 20(42), 5991-6000.
[http://dx.doi.org/10.1038/sj.onc.1204833 ] [PMID: 11593406]
[29]
Bagca, B.G.; Ozalp, O.; Kurt, C.C.; Mutlu, Z.; Saydam, G.; Gunduz, C.; Avci, C.B. Ruxolitinib induces autophagy in chronic myeloid leukemia cells. Tumour Biol., 2016, 37(2), 1573-1579.
[http://dx.doi.org/10.1007/s13277-015-3947-4 ] [PMID: 26298727]
[30]
Lamy, L.; Ngo, V.N.; Emre, N.C.T.; Shaffer, A.L., III; Yang, Y.; Tian, E.; Nair, V.; Kruhlak, M.J.; Zingone, A.; Landgren, O.; Staudt, L.M. Control of autophagic cell death by caspase-10 in multiple myeloma. Cancer Cell, 2013, 23(4), 435-449.
[http://dx.doi.org/10.1016/j.ccr.2013.02.017 ] [PMID: 23541952]
[31]
Qin, B.; Zhou, Z.; He, J.; Yan, C.; Ding, S. IL-6 inhibits starvation-induced autophagy via the STAT3/Bcl-2 signaling pathway. Sci. Rep., 2015, 5, 15701.
[http://dx.doi.org/10.1038/srep15701 ] [PMID: 26549519]
[32]
Yun, Z.; Zhichao, J.; Hao, Y.; Ou, J.; Ran, Y.; Wen, D.; Qun, S. Targeting autophagy in multiple myeloma. Leuk. Res., 2017, 59, 97-104.
[http://dx.doi.org/10.1016/j.leukres.2017.06.002 ] [PMID: 28599191]