Mutant Kras as a Biomarker Plays a Favorable Role in FL118-Induced Apoptosis, Reactive Oxygen Species (ROS) Production and Modulation of Survivin, Mcl-1 and XIAP in Human Bladder Cancer
Abstract
:Simple Summary
Abstract
1. Introduction
2. Materials and Methods
2.1. Reagents and Antibodies
2.2. Cell Culture
2.3. MTT Assay
2.4. Immunoblotting
2.5. Lentiviral shRNA-Mediated Knockdown of Kras and Puromycin Selection
2.6. Overexpression of KrasG12V in HT1376 Bladder Cancer Cells
2.7. Reactive Oxygen Species (ROS) Assay
2.8. Proteomics Analysis of HT1376 versus UMUC3 Cells after FL118 Treatment
2.9. Human Bladder Cancer Xenograft Tumor Mouse Model for FL118 Efficacy Testing
2.10. Statistical Analysis
3. Results
3.1. Differential Inhibitory Effects of FL118 on Viability and Growth of Bladder Cancer Cells with Distinct Ras Statuses
3.2. Human Bladder Cancer Cells with Different Ras Statuses Exhibit Differential Sensitivity to FL118-Induced Apoptosis
3.3. Differential Inhibition of the IAP and Bcl-2 Family Proteins by FL118 Is Associated with FL118 Sensitivity to Bladder Cancer Cells with Different Genetic Backgrounds
3.4. AKT and ERK1/2 Signaling Pathways May Not Play a Major Role in FL118 Differential Sensitivity in Bladder Cancer Cells
3.5. Inhibition of Top1 Expression Is Independent of FL118 Sensitivity or Resistance in Bladder Cancer Cells
3.6. Mutant Kras in Bladder Cancer Cells Plays an Important Role in the Increase of FL118 Anticancer Cell Activity
3.7. FL118 Treatment Increases the Generation of Reactive Oxygen Species (ROS) in Ras-Mutated Bladder Cancer Cells
3.8. Proteomics Analysis Indicates That FL118 Treatment Induced a Profound and Opposed Kras-Relevant Protein Signaling Changes in UMUC3 Cells versus in HT1376 Cells
3.9. UMUC3, but Not HT1376 Bladder Cancer Cell-Derived Xenograft Tumor Exhibits High Sensitivity to FL118 Treatment in Animal Models
4. Discussion
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
- Kamat, A.M.; Hahn, N.M.; Efstathiou, J.A.; Lerner, S.P.; Malmstrom, P.U.; Choi, W.; Guo, C.C.; Lotan, Y.; Kassouf, W. Bladder cancer. Lancet 2016, 388, 2796–2810. [Google Scholar] [CrossRef]
- Knowles, M.A.; Hurst, C.D. Molecular biology of bladder cancer: New insights into pathogenesis and clinical diversity. Nat. Rev. Cancer 2015, 15, 25–41. [Google Scholar] [CrossRef] [PubMed]
- Anastasiadis, A.; de Reijke, T.M. Best practice in the treatment of nonmuscle invasive bladder cancer. Ther. Adv. Urol. 2012, 4, 13–32. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Ghosh, M.; Brancato, S.J.; Agarwal, P.K.; Apolo, A.B. Targeted therapies in urothelial carcinoma. Curr. Opin. Oncol. 2014, 26, 305–320. [Google Scholar] [CrossRef]
- Bellmunt, J.; Petrylak, D.P. New therapeutic challenges in advanced bladder cancer. Semin. Oncol. 2012, 39, 598–607. [Google Scholar] [CrossRef]
- Wong, Y.N.; Litwin, S.; Vaughn, D.; Cohen, S.; Plimack, E.R.; Lee, J.; Song, W.; Dabrow, M.; Brody, M.; Tuttle, H.; et al. Phase II trial of cetuximab with or without paclitaxel in patients with advanced urothelial tract carcinoma. J. Clin. Oncol. 2012, 30, 3545–3551. [Google Scholar] [CrossRef] [Green Version]
- Pruthi, R.S.; Nielsen, M.; Heathcote, S.; Wallen, E.M.; Rathmell, W.K.; Godley, P.; Whang, Y.; Fielding, J.; Schultz, H.; Grigson, G.; et al. A phase II trial of neoadjuvant erlotinib in patients with muscle-invasive bladder cancer undergoing radical cystectomy: Clinical and pathological results. BJU Int. 2010, 106, 349–354. [Google Scholar] [CrossRef]
- van Kessel, K.E.; Zuiverloon, T.C.; Alberts, A.R.; Boormans, J.L.; Zwarthoff, E.C. Targeted therapies in bladder cancer: An overview of in vivo research. Nat. Rev. Urol. 2015, 12, 681–694. [Google Scholar] [CrossRef]
- Soloway, M.S. Bladder cancer: Lack of progress in bladder cancer—What are the obstacles? Nat. Rev. Urol. 2013, 10, 5–6. [Google Scholar] [CrossRef]
- von der Maase, H.; Sengelov, L.; Roberts, J.T.; Ricci, S.; Dogliotti, L.; Oliver, T.; Moore, M.J.; Zimmermann, A.; Arning, M. Long-term survival results of a randomized trial comparing gemcitabine plus cisplatin, with methotrexate, vinblastine, doxorubicin, plus cisplatin in patients with bladder cancer. J. Clin. Oncol. 2005, 23, 4602–4608. [Google Scholar] [CrossRef]
- Montazeri, K.; Bellmunt, J. Erdafitinib for the treatment of metastatic bladder cancer. Expert Rev. Clin. Pharmacol. 2019, 1–6. [Google Scholar] [CrossRef]
- Ewald, J.A.; Downs, T.M.; Cetnar, J.P.; Ricke, W.A. Expression microarray meta-analysis identifies genes associated with Ras/MAPK and related pathways in progression of muscle-invasive bladder transition cell carcinoma. PLoS ONE 2013, 8, e55414. [Google Scholar] [CrossRef] [Green Version]
- McConkey, D.J.; Lee, S.; Choi, W.; Tran, M.; Majewski, T.; Lee, S.; Siefker-Radtke, A.; Dinney, C.; Czerniak, B. Molecular genetics of bladder cancer: Emerging mechanisms of tumor initiation and progression. Urol. Oncol. 2010, 28, 429–440. [Google Scholar] [CrossRef] [Green Version]
- Wu, X.R. Urothelial tumorigenesis: A tale of divergent pathways. Nat. Rev. Cancer 2005, 5, 713–725. [Google Scholar] [CrossRef]
- Jebar, A.H.; Hurst, C.D.; Tomlinson, D.C.; Johnston, C.; Taylor, C.F.; Knowles, M.A. FGFR3 and Ras gene mutations are mutually exclusive genetic events in urothelial cell carcinoma. Oncogene 2005, 24, 5218–5225. [Google Scholar] [CrossRef] [Green Version]
- Ling, X.; Cao, S.; Cheng, Q.; Keefe, J.T.; Rustum, Y.M.; Li, F. A Novel Small Molecule FL118 That Selectively Inhibits Survivin, Mcl-1, XIAP and cIAP2 in a p53-Independent Manner, Shows Superior Antitumor Activity. PLoS ONE 2012, 7, e45571. [Google Scholar] [CrossRef] [Green Version]
- Santha, S.; Viswakarma, N.; Das, S.; Rana, A.; Rana, B. Tumor Necrosis Factor-related Apoptosis-inducing Ligand (TRAIL)-Troglitazone-induced Apoptosis in Prostate Cancer Cells Involve AMP-activated Protein Kinase. J. Biol. Chem. 2015, 290, 21865–21875. [Google Scholar] [CrossRef] [Green Version]
- Ling, X.; Calinski, D.; Chanan-Khan, A.A.; Zhou, M.; Li, F. Cancer cell sensitivity to bortezomib is associated with survivin expression and p53 status but not cancer cell types. J. Exp. Clin. Cancer Res. 2010, 29, 8. [Google Scholar] [CrossRef] [Green Version]
- Santha, S.; Bommareddy, A.; Rule, B.; Guillermo, R.; Kaushik, R.S.; Young, A.; Dwivedi, C. Antineoplastic effects of alpha-santalol on estrogen receptor-positive and estrogen receptor-negative breast cancer cells through cell cycle arrest at G2/M phase and induction of apoptosis. PLoS ONE 2013, 8, e56982. [Google Scholar] [CrossRef]
- Ling, X.; Bernacki, R.J.; Brattain, M.G.; Li, F. Induction of survivin expression by taxol (paclitaxel) is an early event which is independent on taxol-mediated G2/M arrest. J. Biol. Chem. 2004, 279, 15196–15203. [Google Scholar] [CrossRef] [Green Version]
- Rabi, T.; Li, F. Multiple mechanisms involved in a low concentration of FL118 enhancement of AMR-MeOAc to induce pancreatic cancer cell apoptosis and growth inhibition. Am. J. Cancer Res. 2018, 8, 2267–2283. [Google Scholar] [PubMed]
- Shen, X.; Shen, S.; Li, J.; Hu, Q.; Nie, L.; Tu, C.; Wang, X.; Orsburn, B.; Wang, J.; Qu, J. An IonStar Experimental Strategy for MS1 Ion Current-Based Quantification Using Ultrahigh-Field Orbitrap: Reproducible, In-Depth, and Accurate Protein Measurement in Large Cohorts. J. Proteome Res. 2017, 16, 2445–2456. [Google Scholar] [CrossRef] [PubMed]
- Huang da, W.; Sherman, B.T.; Lempicki, R.A. Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources. Nat. Protoc. 2009, 4, 44–57. [Google Scholar] [CrossRef] [PubMed]
- de Hoon, M.J.; Imoto, S.; Nolan, J.; Miyano, S. Open source clustering software. Bioinformatics 2004, 20, 1453–1454. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Subramanian, A.; Tamayo, P.; Mootha, V.K.; Mukherjee, S.; Ebert, B.L.; Gillette, M.A.; Paulovich, A.; Pomeroy, S.L.; Golub, T.R.; Lander, E.S.; et al. Gene set enrichment analysis: A knowledge-based approach for interpreting genome-wide expression profiles. Proc. Natl. Acad. Sci. USA 2005, 102, 15545–15550. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Mootha, V.K.; Lindgren, C.M.; Eriksson, K.F.; Subramanian, A.; Sihag, S.; Lehar, J.; Puigserver, P.; Carlsson, E.; Ridderstrale, M.; Laurila, E.; et al. PGC-1alpha-responsive genes involved in oxidative phosphorylation are coordinately downregulated in human diabetes. Nat. Genet. 2003, 34, 267–273. [Google Scholar] [CrossRef] [PubMed]
- Ling, X.; Li, F. Use of the FL118 Core Chemical Structure Platform to Generate FL118 Derivatives for Treatment of Human Disease (PCT/US2015/022095). 2015. Available online: https://patentswarm.com/patents/US10344037B2 as well as https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2015148415 (accessed on 18 November 2020).
- Earl, J.; Rico, D.; Carrillo-de-Santa-Pau, E.; Rodriguez-Santiago, B.; Mendez-Pertuz, M.; Auer, H.; Gomez, G.; Grossman, H.B.; Pisano, D.G.; Schulz, W.A.; et al. The UBC-40 Urothelial Bladder Cancer cell line index: A genomic resource for functional studies. BMC Genom. 2015, 16, 403. [Google Scholar] [CrossRef] [Green Version]
- Fearon, E.R. Molecular genetics of colorectal cancer. Annu. Rev. Pathol. 2011, 6, 479–507. [Google Scholar] [CrossRef]
- Cox, A.D.; Fesik, S.W.; Kimmelman, A.C.; Luo, J.; Der, C.J. Drugging the undruggable RAS: Mission possible? Nat. Rev. Drug Discov. 2014, 13, 828–851. [Google Scholar] [CrossRef] [Green Version]
- Zhao, J.; Ling, X.; Cao, S.; Liu, X.; Wan, S.; Jiang, T.; Li, F. Antitumor activity of FL118, a survivin, Mcl-1, XIAP, cIAP2 selective inhibitor, is highly dependent on its primary structure and steric configuration. Mol. Pharm. 2014, 11, 457–467. [Google Scholar] [CrossRef]
- Asanuma, H.; Torigoe, T.; Kamiguchi, K.; Hirohashi, Y.; Ohmura, T.; Hirata, K.; Sato, M.; Sato, N. Survivin expression is regulated by coexpression of human epidermal growth factor receptor 2 and epidermal growth factor receptor via phosphatidylinositol 3-kinase/AKT signaling pathway in breast cancer cells. Cancer Res. 2005, 65, 11018–11025. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Xing, H.; Weng, D.; Chen, G.; Tao, W.; Zhu, T.; Yang, X.; Meng, L.; Wang, S.; Lu, Y.; Ma, D. Activation of fibronectin/PI-3K/Akt2 leads to chemoresistance to docetaxel by regulating survivin protein expression in ovarian and breast cancer cells. Cancer Lett. 2008, 261, 108–119. [Google Scholar] [CrossRef] [PubMed]
- Ye, Q.; Cai, W.; Zheng, Y.; Evers, B.M.; She, Q.B. ERK and AKT signaling cooperate to translationally regulate survivin expression for metastatic progression of colorectal cancer. Oncogene 2014, 33, 1828–1839. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Sun, L.; Zhao, Y.; Shi, H.; Ma, C.; Wei, L. LMP-1 induces survivin expression to inhibit cell apoptosis through the NF-kappaB and PI3K/Akt signaling pathways in nasal NK/T-cell lymphoma. Oncol. Rep. 2015, 33, 2253–2260. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Tsubaki, M.; Takeda, T.; Ogawa, N.; Sakamoto, K.; Shimaoka, H.; Fujita, A.; Itoh, T.; Imano, M.; Ishizaka, T.; Satou, T.; et al. Overexpression of survivin via activation of ERK1/2, Akt, and NF-kappaB plays a central role in vincristine resistance in multiple myeloma cells. Leuk. Res. 2015, 39, 445–452. [Google Scholar] [CrossRef] [PubMed]
- Carter, B.Z.; Mak, D.; Schober, W.D.; Cabreira-Hansen, M.; Beran, M.; McQueen, T.; Chen, W.; Andreeff, M. Regulation of survivin expression through Bcr-Abl/MAPK cascade: Targeting survivin overcomes Imatinib resistance and increases Imatinib sensitivity in Imatinib responsive CML cells. Blood 2006, 107, 1555–1563. [Google Scholar] [CrossRef] [PubMed]
- Zhang, Y.; Chen, H.X.; Zhou, S.Y.; Wang, S.X.; Zheng, K.; Xu, D.D.; Liu, Y.T.; Wang, X.Y.; Wang, X.; Yan, H.Z.; et al. Sp1 and c-Myc modulate drug resistance of leukemia stem cells by regulating survivin expression through the ERK-MSK MAPK signaling pathway. Mol. Cancer 2015, 14, 56. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Sugimoto, Y.; Tsukahara, S.; Oh-hara, T.; Isoe, T.; Tsuruo, T. Decreased expression of DNA topoisomerase I in camptothecin-resistant tumor cell lines as determined by a monoclonal antibody. Cancer Res. 1990, 50, 6925–6930. [Google Scholar]
- Kanzawa, F.; Sugimoto, Y.; Minato, K.; Kasahara, K.; Bungo, M.; Nakagawa, K.; Fujiwara, Y.; Liu, L.F.; Saijo, N. Establishment of a camptothecin analogue (CPT-11)-resistant cell line of human non-small cell lung cancer: Characterization and mechanism of resistance. Cancer Res. 1990, 50, 5919–5924. [Google Scholar]
- Woessner, R.D.; Eng, W.K.; Hofmann, G.A.; Rieman, D.J.; McCabe, F.L.; Hertzberg, R.P.; Mattern, M.R.; Tan, K.B.; Johnson, R.K. Camptothecin hyper-resistant P388 cells: Drug-dependent reduction in topoisomerase I content. Oncol. Res. 1992, 4, 481–488. [Google Scholar]
- Ando, K.; Shah, A.K.; Sachdev, V.; Kleinstiver, B.P.; Taylor-Parker, J.; Welch, M.M.; Hu, Y.; Salgia, R.; White, F.M.; Parvin, J.D.; et al. Camptothecin resistance is determined by the regulation of topoisomerase I degradation mediated by ubiquitin proteasome pathway. Oncotarget 2017, 8, 43733–43751. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Sugimoto, Y.; Tsukahara, S.; Oh-hara, T.; Liu, L.F.; Tsuruo, T. Elevated expression of DNA topoisomerase II in camptothecin-resistant human tumor cell lines. Cancer Res. 1990, 50, 7962–7965. [Google Scholar] [PubMed]
- Desai, S.D.; Li, T.K.; Rodriguez-Bauman, A.; Rubin, E.H.; Liu, L.F. Ubiquitin/26S proteasome-mediated degradation of topoisomerase I as a resistance mechanism to camptothecin in tumor cells. Cancer Res. 2001, 61, 5926–5932. [Google Scholar] [PubMed]
- Kapoor, R.; Slade, D.L.; Fujimori, A.; Pommier, Y.; Harker, W.G. Altered topoisomerase I expression in two subclones of human CEM leukemia selected for resistance to camptothecin. Oncol. Res. 1995, 7, 83–95. [Google Scholar]
- Liao, Z.; Robey, R.W.; Guirouilh-Barbat, J.; To, K.K.; Polgar, O.; Bates, S.E.; Pommier, Y. Reduced expression of DNA topoisomerase I in SF295 human glioblastoma cells selected for resistance to homocamptothecin and diflomotecan. Mol. Pharmacol. 2008, 73, 490–497. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Kotoh, S.; Naito, S.; Yokomizo, A.; Kumazawa, J.; Asakuno, K.; Kohno, K.; Kuwano, M. Increased expression of DNA topoisomerase I gene and collateral sensitivity to camptothecin in human cisplatin-resistant bladder cancer cells. Cancer Res. 1994, 54, 3248–3252. [Google Scholar]
- Sakai, A.; Kasahara, K.; Ohmori, T.; Kimura, H.; Sone, T.; Fujimura, M.; Nakao, S. MET increases the sensitivity of gefitinib-resistant cells to SN-38, an active metabolite of irinotecan, by up-regulating the topoisomerase I activity. J. Thorac. Oncol. 2012, 7, 1337–1344. [Google Scholar] [CrossRef] [Green Version]
- Smith, P.J.; Makinson, T.A.; Watson, J.V. Enhanced sensitivity to camptothecin in ataxia-telangiectasia cells and its relationship with the expression of DNA topoisomerase I. Int. J. Radiat. Biol. 1989, 55, 217–231. [Google Scholar] [CrossRef]
- Li, F.; Ling, X.; Harris, D.L.; Liao, J.; Wang, Y.; Westover, D.; Jiang, G.; Xu, B.; Boland, P.M.; Jin, C. Topoisomerase I (Top1): A major target of FL118 for its antitumor efficacy or mainly involved in its side effects of hematopoietic toxicity? Am. J. Cancer Res. 2017, 7, 370–382. [Google Scholar]
- Park, M.T.; Kim, M.J.; Suh, Y.; Kim, R.K.; Kim, H.; Lim, E.J.; Yoo, K.C.; Lee, G.H.; Kim, Y.H.; Hwang, S.G.; et al. Novel signaling axis for ROS generation during K-Ras-induced cellular transformation. Cell Death Differ. 2014, 21, 1185–1197. [Google Scholar] [CrossRef] [Green Version]
- Suh, Y.; Lee, S.J. KRAS-driven ROS promote malignant transformation. Mol. Cell Oncol. 2015, 2, e968059. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Li, F. Compositions and Methods for Identifying Agents that Alter Expression of Survivin. US Patent 7,569,221 B2, 4 August 2009. [Google Scholar]
- Ling, X.; Xu, C.; Fan, C.; Zhong, K.; Li, F.; Wang, X. FL118 Induces p53-Dependent Senescence in Colorectal Cancer Cells by Promoting Degradation of MdmX. Cancer Res. 2014, 74, 7487–7497. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Houghton, P.J.; Germain, G.S.; Harwood, F.C.; Schuetz, J.D.; Stewart, C.F.; Buchdunger, E.; Traxler, P. Imatinib mesylate is a potent inhibitor of the ABCG2 (BCRP) transporter and reverses resistance to topotecan and SN-38 in vitro. Cancer Res. 2004, 64, 2333–2337. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Su, Y.; Hu, P.; Lee, S.H.; Sinko, P.J. Using novobiocin as a specific inhibitor of breast cancer resistant protein (BCRP/ABCG2) to assess the role of transporter in the absorption and disposition of topotecan. J. Pharm. Pharm. Sci. 2007, 10, 519–536. [Google Scholar] [CrossRef] [Green Version]
- Su, Y.; Lee, S.H.; Sinko, P.J. Inhibition of efflux transporter ABCG2/BCRP does not restore mitoxantrone sensitivity in irinotecan-selected human leukemia CPT-K5 cells: Evidence for multifactorial multidrug resistance. Eur. J. Pharm. Sci. Off. J. Eur. Fed. Pharm. Sci. 2006, 29, 102–110. [Google Scholar] [CrossRef]
- Yoshikawa, M.; Ikegami, Y.; Sano, K.; Yoshida, H.; Mitomo, H.; Sawada, S.; Ishikawa, T. Transport of SN-38 by the wild type of human ABC transporter ABCG2 and its inhibition by quercetin, a natural flavonoid. J. Exp. Ther. Oncol. 2004, 4, 25–35. [Google Scholar]
- Shishido, Y.; Ueno, S.; Yamazaki, R.; Nagaoka, M.; Matsuzaki, T. ABCG2 inhibitor YHO-13351 sensitizes cancer stem/initiating-like side population cells to irinotecan. Anticancer Res. 2013, 33, 1379–1386. [Google Scholar]
- Maliepaard, M.; van Gastelen, M.A.; de Jong, L.A.; Pluim, D.; van Waardenburg, R.C.; Ruevekamp-Helmers, M.C.; Floot, B.G.; Schellens, J.H. Overexpression of the BCRP/MXR/ABCP gene in a topotecan-selected ovarian tumor cell line. Cancer Res. 1999, 59, 4559–4563. [Google Scholar]
- Kruijtzer, C.M.; Beijnen, J.H.; Rosing, H.; ten Bokkel Huinink, W.W.; Schot, M.; Jewell, R.C.; Paul, E.M.; Schellens, J.H. Increased oral bioavailability of topotecan in combination with the breast cancer resistance protein and P-glycoprotein (Pgp) inhibitor GF120918. J. Clin. Oncol. Off. J. Am. Soc. Clin. Oncol. 2002, 20, 2943–2950. [Google Scholar] [CrossRef]
- de Vries, N.A.; Zhao, J.; Kroon, E.; Buckle, T.; Beijnen, J.H.; van Tellingen, O. P-glycoprotein (Pgp) and breast cancer resistance protein (BCRP): Two dominant transporters working together in limiting the brain penetration of topotecan. Clin. Cancer Res. Off. J. Am. Assoc. Cancer Res. 2007, 13, 6440–6449. [Google Scholar] [CrossRef] [Green Version]
- Takeba, Y.; Sekine, S.; Kumai, T.; Matsumoto, N.; Nakaya, S.; Tsuzuki, Y.; Yanagida, Y.; Nakano, H.; Asakura, T.; Ohtsubo, T.; et al. Irinotecan-induced apoptosis is inhibited by increased P-glycoprotein expression and decreased p53 in human hepatocellular carcinoma cells. Biol. Pharm. Bull. 2007, 30, 1400–1406. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Tagen, M.; Zhuang, Y.; Zhang, F.; Harstead, K.E.; Shen, J.; Schaiquevich, P.; Fraga, C.H.; Panetta, J.C.; Waters, C.M.; Stewart, C.F. P-glycoprotein, but not multidrug resistance protein 4, plays a role in the systemic clearance of irinotecan and SN-38 in mice. Drug Metab. Lett. 2010, 4, 195–201. [Google Scholar] [CrossRef] [PubMed]
- Filipski, E.; Berland, E.; Ozturk, N.; Guettier, C.; van der Horst, G.T.; Levi, F.; Okyar, A. Optimization of irinotecan chronotherapy with P-glycoprotein inhibition. Toxicol. Appl. Pharmacol. 2014, 274, 471–479. [Google Scholar] [CrossRef] [PubMed]
- Hendricks, C.B.; Rowinsky, E.K.; Grochow, L.B.; Donehower, R.C.; Kaufmann, S.H. Effect of P-glycoprotein expression on the accumulation and cytotoxicity of topotecan (SK&F 104864), a new camptothecin analogue. Cancer Res. 1992, 52, 2268–2278. [Google Scholar] [PubMed]
- Westover, D.; Ling, X.; Lam, H.; Welch, J.; Jin, C.; Gongora, C.; Del Rio, M.; Wani, M.; Li, F. FL118, a novel camptothecin derivative, is insensitive to ABCG2 expression and shows improved efficacy in comparison with irinotecan in colon and lung cancer models with ABCG2-induced resistance. Mol. Cancer 2015, 14, 92. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Ling, X.; Liu, X.J.; Zhong, K.; Smith, N.; Prey, J.; Li, F. FL118, a novel camptothecin analogue, overcomes irinotecan and topotecan resistance in human tumor xenograft models. Am. J. Transl. Res. 2015, 7, 1765–1781. [Google Scholar]
- Ling, X.; Wu, W.; Fan, C.; Xu, C.; Liao, J.; Rich, L.J.; Huang, R.Y.; Repasky, E.A.; Wang, X.; Li, F. An ABCG2 non-substrate anticancer agent FL118 targets drug-resistant cancer stem-like cells and overcomes treatment resistance of human pancreatic cancer. J. Exp. Clin. Cancer Res. 2018, 37, 240. [Google Scholar] [CrossRef] [Green Version]
- Westover, D.; Li, F. New trends for overcoming ABCG2/BCRP-mediated resistance to cancer therapies. J. Exp. Clin. Cancer Res. 2015, 34, 159. [Google Scholar] [CrossRef] [Green Version]
- Szanto, A.; Bognar, Z.; Szigeti, A.; Szabo, A.; Farkas, L.; Gallyas, F., Jr. Critical role of bad phosphorylation by Akt in cytostatic resistance of human bladder cancer cells. Anticancer Res. 2009, 29, 159–164. [Google Scholar]
- Yuge, K.; Kikuchi, E.; Hagiwara, M.; Yasumizu, Y.; Tanaka, N.; Kosaka, T.; Miyajima, A.; Oya, M. Nicotine Induces Tumor Growth and Chemoresistance through Activation of the PI3K/Akt/mTOR Pathway in Bladder Cancer. Mol. Cancer Ther. 2015, 14, 2112–2120. [Google Scholar] [CrossRef] [Green Version]
- Dong, Q.; Fu, L.; Zhao, Y.; Tan, S.; Wang, E. Derlin-1 overexpression confers poor prognosis in muscle invasive bladder cancer and contributes to chemoresistance and invasion through PI3K/AKT and ERK/MMP signaling. Oncotarget 2017, 8, 17059–17069. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Takeuchi, A.; Eto, M.; Shiota, M.; Tatsugami, K.; Yokomizo, A.; Kuroiwa, K.; Itsumi, M.; Naito, S. Sunitinib enhances antitumor effects against chemotherapy-resistant bladder cancer through suppression of ERK1/2 phosphorylation. Int J. Oncol. 2012, 40, 1691–1696. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Huang, L.; Luan, T.; Chen, Y.; Bao, X.; Huang, Y.; Fu, S.; Wang, H.; Wang, J. LASS2 regulates invasion and chemoresistance via ERK/Drp1 modulated mitochondrial dynamics in bladder cancer cells. J. Cancer 2018, 9, 1017–1024. [Google Scholar] [CrossRef] [PubMed]
- Shrader, M.; Pino, M.S.; Lashinger, L.; Bar-Eli, M.; Adam, L.; Dinney, C.P.; McConkey, D.J. Gefitinib reverses TRAIL resistance in human bladder cancer cell lines via inhibition of AKT-mediated X-linked inhibitor of apoptosis protein expression. Cancer Res. 2007, 67, 1430–1435. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Wolff, D.; Lee, M.H.; Jothi, M.; Mal, M.; Li, F.; Mal, A.K. Camptothecin exhibits topoisomerase1-independent KMT1A suppression and myogenic differentiation in alveolar rhabdomyosarcoma cells. Oncotarget 2018, 9, 25796–25807. [Google Scholar] [CrossRef] [PubMed]
- Bennett, R.P.; Stewart, R.A.; Hogan, P.A.; Ptak, R.G.; Mankowski, M.K.; Hartman, T.L.; Buckheit, R.W., Jr.; Snyder, B.A.; Salter, J.D.; Morales, G.A.; et al. An analog of camptothecin inactive against Topoisomerase I is broadly neutralizing of HIV-1 through inhibition of Vif-dependent APOBEC3G degradation. Antiviral Res. 2016, 136, 51–59. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Li, F.; Jiang, T.; Li, Q.; Ling, X. Camptothecin (CPT) and its derivatives are known to target topoisomerase I (Top1) as their mechanism of action: Did we miss something in CPT analogue molecular targets for treating human disease such as cancer? Am. J. Cancer Res. 2017, 7, 2350–2394. [Google Scholar]
- Choudhary, S.; Wang, H.C. Role of reactive oxygen species in proapoptotic ability of oncogenic H-Ras to increase human bladder cancer cell susceptibility to histone deacetylase inhibitor for caspase induction. J. Cancer Res. Clin. Oncol. 2009, 135, 1601–1613. [Google Scholar] [CrossRef]
- Lebedeva, I.V.; Su, Z.Z.; Sarkar, D.; Gopalkrishnan, R.V.; Waxman, S.; Yacoub, A.; Dent, P.; Fisher, P.B. Induction of reactive oxygen species renders mutant and wild-type K-ras pancreatic carcinoma cells susceptible to Ad.mda-7-induced apoptosis. Oncogene 2005, 24, 585–596. [Google Scholar] [CrossRef] [Green Version]
- Wang, H.C.; Choudhary, S. Reactive oxygen species-mediated therapeutic control of bladder cancer. Nat. Rev. Urol. 2011, 8, 608–616. [Google Scholar] [CrossRef]
- Li, F.; Aljahdali, I.; Ling, X. Cancer therapeutics using survivin BIRC5 as a target: What can we do after over two decades of study? J. Exp. Clin. Cancer Res. 2019, 38, 368. [Google Scholar] [CrossRef] [PubMed] [Green Version]
Cell Line | Kras/Hras/Nras Status | IC50 * |
---|---|---|
HT1376 | Wild type | >200 nM |
T-24 | Hras mutation | ~13 nM |
UMUC3 | Kras mutation | ~3 nM |
RT112 | Wild type | >160 nM |
253 J B-V | Wild type | >110 nM |
TCCSUP (HTB-5) | Wild type | >160 nM |
SNU-C2B (CRC) | Kras mutation | ~2.7 nM |
HCT116 (CRC). | Kras mutation | ~0.51 nM |
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. |
© 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
Share and Cite
Santha, S.; Ling, X.; Aljahdali, I.A.M.; Rasam, S.S.; Wang, X.; Liao, J.; Wang, J.; Fountzilas, C.; Li, Q.; Qu, J.; et al. Mutant Kras as a Biomarker Plays a Favorable Role in FL118-Induced Apoptosis, Reactive Oxygen Species (ROS) Production and Modulation of Survivin, Mcl-1 and XIAP in Human Bladder Cancer. Cancers 2020, 12, 3413. https://doi.org/10.3390/cancers12113413
Santha S, Ling X, Aljahdali IAM, Rasam SS, Wang X, Liao J, Wang J, Fountzilas C, Li Q, Qu J, et al. Mutant Kras as a Biomarker Plays a Favorable Role in FL118-Induced Apoptosis, Reactive Oxygen Species (ROS) Production and Modulation of Survivin, Mcl-1 and XIAP in Human Bladder Cancer. Cancers. 2020; 12(11):3413. https://doi.org/10.3390/cancers12113413
Chicago/Turabian StyleSantha, Sreevidya, Xiang Ling, Ieman A. M. Aljahdali, Sailee S. Rasam, Xue Wang, Jianqun Liao, Jue Wang, Christos Fountzilas, Qingyong Li, Jun Qu, and et al. 2020. "Mutant Kras as a Biomarker Plays a Favorable Role in FL118-Induced Apoptosis, Reactive Oxygen Species (ROS) Production and Modulation of Survivin, Mcl-1 and XIAP in Human Bladder Cancer" Cancers 12, no. 11: 3413. https://doi.org/10.3390/cancers12113413
APA StyleSantha, S., Ling, X., Aljahdali, I. A. M., Rasam, S. S., Wang, X., Liao, J., Wang, J., Fountzilas, C., Li, Q., Qu, J., & Li, F. (2020). Mutant Kras as a Biomarker Plays a Favorable Role in FL118-Induced Apoptosis, Reactive Oxygen Species (ROS) Production and Modulation of Survivin, Mcl-1 and XIAP in Human Bladder Cancer. Cancers, 12(11), 3413. https://doi.org/10.3390/cancers12113413