Metronomic Combination Chemotherapy Using Everolimus and Etoposide for the Treatment of non‐Hodgkin Lymphoma
Open accessAbstract
Patients with Non-Hodgkin lymphoma (NHL) treated by conventional chemotherapeutic drugs usually require a long recovery period. However, metronomic combination chemotherapy (MCC) enhances therapeutic efficacy and decreases side effects in the treatment of NHL. In this study, we tested and compared the effects of metronomic chemotherapy (MC) using podophyllotoxin derivative etoposide (VP-16) alone and that of MCC using both VP-16 and everolimus (RAD001) in the treatment of NHL. Two types of NHL cells, OCI-LY-10 and SU-DHL-6, were employed for the experiments. Cell proliferation, apoptosis, and cell senescence were measured to test the effects of drugs in each experiment. In addition, the influences of MC and MCC on the cell cycle and autophagy pathway were evaluated to study the functional mechanisms behind their effects. Finally, we conducted analyses of the growth inhibitory effect and synergistic activity for different MCC. The results showed that MC using low-dose VP-16 alone demonstrated strong treatment effects in terms of inducing apoptosis, cell senescence, and reducing tumor cell proliferation, and this treatment also led to changes of the cell cycle. Compared with MC, MCC using VP-16 and RAD001 together demonstrated even stronger treatment effects, with both the cell cycle and autophagy-related proteins being affected. Considering the synergistic activity, our results showed the MCC of VP-16 48 hours + RAD001 24 hours is the optimal method for treating NHL.
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mTOR inhibitors could inhibit tumor progression as having a complex modifying role on metabolism.
“mTOR inhibitors could inhibit tumor progression as having a complex modifying role on metabolism [108–113].”
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Cites
mTOR as a central hub of nutrient signalling and cell growth
Kim, J., & Guan, K. (2018) · Nature Cell Biology · doi:10.1038/s41556-018-0205-1 · Cited by 1,067 · see citing works
Etoposide: four decades of development of a topoisomerase II inhibitor
Hande, K. R. (1998) · European Journal of Cancer · doi:10.1016/s0959-8049(98)00228-7 · Cited by 948 · see citing works
Gatenby, R. A., Silva, A. S., Gillies, R. J., & Frieden, B. R. (2009) · Cancer Research · doi:10.1158/0008-5472.can-08-3658 · Cited by 861 · see citing works
mTOR as Regulator of Lifespan, Aging, and Cellular Senescence: A Mini-Review
Weichhart, T. (2018) · Gerontology · doi:10.1159/000484629 · Cited by 596 · see citing works
TORC1 inhibition enhances immune function and reduces infections in the elderly
Mannick, J. B., Morris, M., Hockey, H.-U. P., Roma, G., Beibel, M., Kulmatycki, K., Watkins, M., Shavlakadze, T., Zhou, W., Quinn, D., et al. (2018) · Science Translational Medicine · doi:10.1126/scitranslmed.aaq1564 · Cited by 496 · see citing works
Metronomics: towards personalized chemotherapy?
André, N., Carré, M., & Pasquier, E. (2014) · Nature Reviews Clinical Oncology · doi:10.1038/nrclinonc.2014.89 · Cited by 316 · see citing works
Granato, M., Rizzello, C., Montani, M. S. G., Cuomo, L., Vitillo, M., Santarelli, R., Gonnella, R., D’Orazi, G., Faggioni, A., & Cirone, M. (2017) · The Journal of Nutritional Biochemistry · doi:10.1016/j.jnutbio.2016.12.011 · Cited by 261 · see citing works
Qian, W., Liu, J., Jin, J., Ni, W., & Xu, W. (2006) · Leukemia Research · doi:10.1016/j.leukres.2006.06.021 · Cited by 203 · see citing works
Kummar, S., Ji, J. J., Morgan, R. J., Lenz, H.-J., Puhalla, S. L., Belani, C. P., Gandara, D. R., Allen, D. E., Kiesel, B. F., Beumer, J. H., et al. (2012) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-11-2821 · Cited by 200 · see citing works
Jing, K., Song, K., Shin, S., Kim, N., Jeong, S., Oh, H.-R., Park, J.-H., Seo, K.-S., Heo, J. Y., Han, J., et al. (2011) · Autophagy · doi:10.4161/auto.7.11.16658 · Cited by 199 · see citing works
Barta, S. K., Xue, X., Wang, D., Tamari, R., Lee, J. Y., Mounier, N., Kaplan, L. D., Ribera, J., Spina, M., Tirelli, U., et al. (2013) · Blood · doi:10.1182/blood-2013-04-498964 · Cited by 191 · see citing works
Kornblum, N. S., Zhao, F., Manola, J. B., Klein, P., Ramaswamy, B., Brufsky, A., Stella, P. J., Burnette, B. L., Telli, M. L., Makower, D., et al. (2018) · Journal of Clinical Oncology · doi:10.1200/jco.2017.76.9331 · Cited by 191 · see citing works
Metronomic chemotherapy and immunotherapy in cancer treatment
Chen, Y., Chang, M.-C., & Cheng, W. (2017) · Cancer Letters · doi:10.1016/j.canlet.2017.01.040 · Cited by 162 · see citing works
mTOR: A Cellular Regulator Interface in Health and Disease
Boutouja, F., Stiehm, C. M., & Platta, H. W. (2019) · Cells · doi:10.3390/cells8010018 · Cited by 136 · see citing works
Witzig, T. E., Reeder, C. B., Han, J., LaPlant, B. R., Stenson, M. J., Tun, H. W., Macon, W. R., Ansell, S. M., Habermann, T. M., Inwards, D. J., et al. (2015) · Blood · doi:10.1182/blood-2015-02-629543 · Cited by 114 · see citing works
Fazio, N., Buzzoni, R., Fave, G. D., Tesselaar, M. E. T., Wolin, E. M., Cutsem, E. V., Tomassetti, P., Strosberg, J., Voi, M., Bubuteishvili‐Pacaud, L., et al. (2017) · Cancer Science · doi:10.1111/cas.13427 · Cited by 110 · see citing works
Filippi‐Chiela, E. C., Silva, M. M. B. E., Thomé, M. P. M., & Lenz, G. (2015) · Autophagy · doi:10.1080/15548627.2015.1009795 · Cited by 98 · see citing works
Everolimus in Advanced Pancreatic Neuroendocrine Tumors: The Clinical Experience
Yao, J. C., Phan, A. T., Jehl, V., Shah, G., & Meric‐Bernstam, F. (2013) · Cancer Research · doi:10.1158/0008-5472.can-12-3923 · Cited by 86 · see citing works
Sung, J. Y., Lee, K. Y., Kim, J., & Choi, H. C. (2017) · Experimental Gerontology · doi:10.1016/j.exger.2017.08.001 · Cited by 69 · see citing works
Structural insights into the gating of DNA passage by the topoisomerase II DNA-gate
Chen, S.-F., Huang, N.-L., Lin, J., Wu, C.-C., Wang, Y.-R., Yu, Y.-J., Gilson, M. K., & Chan, N. (2018) · Nature Communications · doi:10.1038/s41467-018-05406-y · Cited by 69 · see citing works
Self-citationChristopoulos, P., Engel-Riedel, W., Grohé, C., Kropf-Sanchen, C., von Pawel, J., Gutz, S., Kollmeier, J., Eberhardt, W., Ukena, D., Baum, V., et al. (2017) · Annals of Oncology · doi:10.1093/annonc/mdx268 · Cited by 67 · see citing works
Liu, M., Zeng, T., Zhang, X., Liu, C., Wu, Z., Yao, L., Xie, C., Xia, H., Lin, Q., Xie, L., et al. (2018) · Nature Communications · doi:10.1038/s41467-018-06556-9 · Cited by 66 · see citing works
Lonetti, A., Cappellini, A., Bertaina, A., Locatelli, F., Pession, A., Buontempo, F., Evangelisti, C., Evangelisti, C., Orsini, E., Zambonin, L., et al. (2016) · Journal of Hematology & Oncology · doi:10.1186/s13045-016-0344-4 · Cited by 62 · see citing works
Johnston, P. B., LaPlant, B. R., McPhail, E. D., Habermann, T. M., Inwards, D. J., Micallef, I. N., Colgan, J. P., Nowakowski, G. S., Ansell, S. M., & Witzig, T. E. (2016) · The Lancet Haematology · doi:10.1016/s2352-3026(16)30040-0 · Cited by 57 · see citing works
Everolimus-based combination therapies for HR+, HER2− metastatic breast cancer
O’Shaughnessy, J., Beck, J. T., & Royce, M. (2018) · Cancer Treatment Reviews · doi:10.1016/j.ctrv.2018.07.013 · Cited by 57 · see citing works
Shao, Y., Huang, C.-C., Lin, S.-D., Hsu, C., & Cheng, A. (2012) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-11-2853 · Cited by 45 · see citing works
Targeting nucleolin for better survival in diffuse large B-cell lymphoma
Jain, N. K., Zhu, H., Khashab, T., Ye, Q., George, B., Mathur, R., Singh, R., Berkova, Z., Wise, J. F., Braun, F., et al. (2017) · Leukemia · doi:10.1038/leu.2017.215 · Cited by 43 · see citing works
Autophagy in Premature Senescent Cells Is Activated via AMPK Pathway
Guo, L., Xie, B., & Mao, Z. (2012) · International Journal of Molecular Sciences · doi:10.3390/ijms13033563 · Cited by 41 · see citing works
Kwak, G., Jo, S. D., Kim, D., Kim, H., Kim, M. G., Kim, K., Kwon, I. C., & Kim, S. H. (2017) · Journal of Controlled Release · doi:10.1016/j.jconrel.2017.08.015 · Cited by 39 · see citing works
Bi, C., Zhang, X., Lu, T., Zhang, X., Wang, X., Meng, B., Zhang, H., Wang, P., Vose, J. M., Chan, W. C., et al. (2017) · Haematologica · doi:10.3324/haematol.2016.159160 · Cited by 32 · see citing works
Combining low-dose or metronomic chemotherapy with anticancer vaccines
Sow, H. S., & Mattarollo, S. R. (2013) · OncoImmunology · doi:10.4161/onci.27058 · Cited by 31 · see citing works
Chung, S. W., Kim, G. C., Kweon, S., Lee, H., Choi, J. U., Mahmud, F., Chang, H. W., Kim, J. W., Son, W., Kim, S. Y., et al. (2018) · Biomaterials · doi:10.1016/j.biomaterials.2018.08.007 · Cited by 27 · see citing works
Autophagy as a pathogenic mechanism and drug target in lymphoproliferative disorders
Pierdominici, M., Barbati, C., Vomero, M., Locatelli, S. L., Carlo‐Stella, C., Ortona, E., & Malorni, W. (2013) · The FASEB Journal · doi:10.1096/fj.13-235655 · Cited by 24 · see citing works
Role of Nitric Oxide in the Chemistry and Anticancer Activity of Etoposide (VP-16,213)
Sinha, B. K., Bhattacharjee, S., Chatterjee, S., Jiang, J., Motten, A. G., Kumar, A., Espey, M. G., & Mason, R. P. (2013) · Chemical Research in Toxicology · doi:10.1021/tx300480q · Cited by 23 · see citing works
Chiang, C.-T., Yeh, P.-Y., Gao, M., Chen, C.-W. D., Yeh, L.-C., Feng, W.-C., Kuo, S., Hsu, C., Lu, Y., & Cheng, A. (2010) · Cancer Letters · doi:10.1016/j.canlet.2010.07.005 · Cited by 23 · see citing works
Zeng, J., Yang, L., Huang, F., Hong, T., Zhihui, H., Lei, J., Sun, H., Lu, Y., & Hao, X. (2016) · Cancer Chemotherapy and Pharmacology · doi:10.1007/s00280-016-3136-1 · Cited by 18 · see citing works
mTORC1 Inhibition Induces Resistance to Methotrexate and 6-Mercaptopurine in Ph+ and Ph-like B-ALL
Vo, T.-T. T., Lee, J. S., Nguyen, D. M., Lui, B., Pandori, W., Khaw, A., Mallya, S., Lu, M., Müschen, M., Konopleva, M. Y., et al. (2017) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-17-0024 · Cited by 15 · see citing works
Therapy-activated stromal cells can dictate tumor fate
Kerbel, R. S., & Shaked, Y. (2016) · The Journal of Experimental Medicine · doi:10.1084/jem.20161845 · Cited by 10 · see citing works
Metronomic chemotherapy for elderly and/or frail patients
Romero, D. (2018) · Nature Reviews Clinical Oncology · doi:10.1038/nrclinonc.2018.33 · Cited by 10 · see citing works
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Sebestyén, A., Kopper, L., Dankó, T., & Tímár, J. (2021) · Pathology and Oncology Research · doi:10.3389/pore.2021.1609802 · Cited by 110 · see citing works
Kashkooli, F. M., & Soltani, M. (2021) · Scientific Reports · doi:10.1038/s41598-021-00989-x · Cited by 44 · see citing works
Cellular senescence signaling in cancer: A novel therapeutic target to combat human malignancies
Fakhri, S., Moradi, S. Z., DeLiberto, L. K., & Bishayee, A. (2022) · Biochemical Pharmacology · doi:10.1016/j.bcp.2022.114989 · Cited by 38 · see citing works
Metronomic chemotherapy in cancer treatment: new wine in an old bottle
Wu, H., Zhou, H.-X., Chen, L., & Wang, S.-S. (2024) · Theranostics · doi:10.7150/thno.95619 · Cited by 20 · see citing works
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Zhang, L., Zhou, S., Zhou, T., Yuan, K., Li, X., & Tang, J. (2020) · Oncology Reports · doi:10.3892/or.2020.7841 · Cited by 14 · see citing works
Cox, M. C., & Bocci, G. (2021) · Cancer Letters · doi:10.1016/j.canlet.2021.10.018 · Cited by 13 · see citing works
Banchi, M., Cox, M. C., & Bocci, G. (2024) · Cancer Letters · doi:10.1016/j.canlet.2024.216900 · Cited by 10 · see citing works
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- Authors
- Wu, K., Sun, X., Wang, C., Gao, T., Sun, P., Wang, Y., Jiang, W., Li, Z., & Huang, J.
- Affiliations
- Sun Yat-sen University (CN)
- Department of Medical Oncology, Sun Yat‐sen University Cancer Center, State Key Laboratory of Oncology in South China Collaborative Innovation Center for Cancer Medicine Guangzhou China
- Venue
- Cancer Medicine
- Publisher
- Wiley
- Published
- 2019-06-20
- Volume
- 8
- Issue
- 10
- Pages
- 4688-4698
- ISSN
- 2045-7634 (ISSN-L)
- PMC
- PMC6712471
- OpenAlex
- W2951823164
- Cited by
- 10
- References
- 39
- Citations by year
- 2025: 1 · 2024: 2 · 2022: 1 · 2021: 4 · 2020: 2
- FWCI
- 1.29
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Cancer Medicine (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- National Natural Science Foundation of China (81472759, 81611130086, 81872902)
- Topics
- Health Sciences › Medicine › Pathology and Forensic Medicine › Lymphoma Diagnosis and Treatment
- Health Sciences › Medicine › Genetics › Chronic Lymphocytic Leukemia Research
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Keywords
- non-Hodgkin lymphoma, metronomic chemotherapy, combination chemotherapy, everolimus, etoposide, podophyllotoxin derivatives, apoptosis, cellular senescence, cell cycle, autophagy, drug synergy
- MeSH terms
- Everolimus, Autophagy-Related Proteins, Antineoplastic Combined Chemotherapy Protocols, Cell Survival, Drug Synergism, Etoposide, Humans, Lymphoma, Non-Hodgkin, Gene Expression Regulation, Neoplastic, Survival Analysis, Treatment Outcome, Cell Line, Tumor, Cell Proliferation, Administration, Metronomic
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