Rapamycin: an anti-cancer immunosuppressant?

Law, Brian K.

doi:10.1016/j.critrevonc.2004.09.009

Cited by 252PI3K/AKT/mTOR signaling in cancerSignaling Pathways in DiseaseAutophagy in Disease and Therapy

Rapamycin: an anti-cancer immunosuppressant?

Law, Brian K.·2005·Critical Reviews in Oncology/Hematology

DOI 10.1016/j.critrevonc.2004.09.009

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Abstract

Rapamycin and its derivatives are promising therapeutic agents with both immunosuppressant and anti-tumor properties. These rapamycin actions are mediated through the specific inhibition of the mTOR protein kinase. mTOR serves as part of an evolutionarily conserved signaling pathway that controls the cell cycle in response to changing nutrient levels. The mTOR signaling network contains a number of tumor suppressor genes including PTEN, LKB1, TSC1, and TSC2, and a number of proto-oncogenes including PI3K, Akt, and eIF4E, and mTOR signaling is constitutively activated in many tumor types. These observations point to mTOR as an ideal target for anti-cancer agents and suggest that rapamycin is such an agent. In fact, early preclinical and clinical studies indicate that rapamycin derivatives have efficacy as anti-tumor agents both alone, and when combined with other modes of therapy. Rapamycin appears to inhibit tumor growth by halting tumor cell proliferation, inducing tumor cell apoptosis, and suppressing tumor angiogenesis. Rapamycin immunosuppressant actions result from the inhibition of T and B cell proliferation through the same mechanisms that rapamycin blocks cancer cell proliferation. Therefore, one might think that rapamycin-induced immunosuppression would be detrimental to the use of rapamycin as an anti-cancer agent. To the contrary, rapamycin decreases the frequency of tumor formation that occurs in organ transplant experiments when combined with the widely used immunosuppressant cyclosporine compared with the tumor incidence observed when cyclosporine is used alone. The available evidence indicates that with respect to tumor growth, rapamycin anti-cancer activities are dominant over rapamycin immunosuppressant effects.

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FKBP-rapamycin inhibits a cyclin-dependent kinase activity and a cyclin D1-Cdk association in early G1 of an osteosarcoma cell line
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Rapamycin inhibition of interleukin-2-dependent p33cdk2 and p34cdc2 kinase activation in T lymphocytes.
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Evidence That Cyclin D1 Mediates Both Growth and Proliferation Downstream of TOR in Hepatocytes
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Molecular cloning and tissue distribution of PHAS-I, an intracellular target for insulin and growth factors.
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Hepatocellular carcinoma caused by loss of heterozygosity in Lkb1 gene knockout mice.
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Somatic Mutations in the Peutz-Jegners (LKB1/STKII) Gene in Sporadic Malignant Melanomas
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Rapamycin (sirolimus) inhibits proliferating cell nuclear antigen expression and blocks cell cycle in the G1 phase in human keratinocyte stem cells.
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Flagged first, then by citations

25 of the 256 references couldn’t be matched to a known paper.

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LKB1-Dependent Signaling Pathways
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Rapamycin causes regression of astrocytomas in tuberous sclerosis complex
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Enhancing the Enrichment of Pharmacophore-Based Target Prediction for the Polypharmacological Profiles of Drugs
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Cancer in the Transplant RecipientPreprint
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Targeting the PI3K/AKT/mTOR and RAF/MEK/ERK pathways for cancer therapy
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Excessive Autophagy Contributes to Neuron Death in Cerebral Ischemia
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Targeting the nucleolus for cancer intervention
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The mTOR pathway is associated with the poor prognosis of human hepatocellular carcinoma
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Autoimmune diseases and immune-checkpoint inhibitors for cancer therapy: Review of the literature and personalized risk-based prevention strategy
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Randomized Controlled Trial of Sirolimus for Renal Transplant Recipients at High Risk for Nonmelanoma Skin Cancer
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Metabolic Cooperation and Competition in the Tumor Microenvironment: Implications for Therapy
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Relating drug–protein interaction network with drug side effects
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Exploiting a precise design of universal synthetic modular regulatory elements to unlock the microbial natural products in Streptomyces
Bai, C., Zhang, Y., Zhao, X., Hu, Y., Xiang, S., Miao, J., Lou, C., & Zhang, L. (2015) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1511027112 · Cited by 201 · see citing works
Hedgehog signalling in skin development and cancer
Athar, M., Tang, X., Lee, J. L., Kopelovich, L., & Kim, A. L. (2006) · Experimental Dermatology · doi:10.1111/j.1600-0625.2006.00473.x · Cited by 197 · see citing works
Targeting the mTOR kinase domain: the second generation of mTOR inhibitors
Zhang, Y.-J., Duan, Y.-W., & Zheng, X.-F. (2011) · Drug Discovery Today · doi:10.1016/j.drudis.2011.02.008 · Cited by 175 · see citing works
Activation of the mTOR Signaling Pathway in Renal Clear Cell Carcinoma
Robb, V. A., Karbowniczek, M., Klein–Szanto, A. J., & Henske, E. P. (2006) · The Journal of Urology · doi:10.1016/j.juro.2006.08.076 · Cited by 165 · see citing works
Expanding therapeutic targets in bladder cancer: the PI3K/Akt/mTOR pathway
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Unexpected applications of secondary metabolites
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An anti-aging drug today: from senescence-promoting genes to anti-aging pill
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DAMPs, ageing, and cancer: The ‘DAMP Hypothesis’
Huang, J., Xie, Y., Sun, X., Zeh, H. J., Kang, R., Lotze, M. T., & Tang, D. (2015) · Ageing Research Reviews · doi:10.1016/j.arr.2014.10.004 · Cited by 144 · see citing works
Validation of anti-aging drugs by treating age-related diseases
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Preserved renal-allograft function and the PD-1 pathway inhibitor nivolumab
Barnett, R., Barta, V. S., & Jhaveri, K. D. (2017) · New England Journal of Medicine · doi:10.1056/nejmc1614298 · Cited by 136 · see citing works
The long and winding road to rational treatment of cancer associated with LKB1/AMPK/TSC/mTORC1 signaling
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FK506-Binding Proteins and Their Diverse Functions
Tong, M., & Jiang, Y. (2015) · Current Molecular Pharmacology · doi:10.2174/1874467208666150519113541 · Cited by 126 · see citing works
PRAS40 Deregulates Apoptosis in Malignant Melanoma
Madhunapantula, S. V., Sharma, A. K., & Robertson, G. P. (2007) · Cancer Research · doi:10.1158/0008-5472.can-06-4234 · Cited by 124 · see citing works
Caloric restriction: Beneficial effects on brain aging and Alzheimer’s disease
Van Cauwenberghe, C., Vandendriessche, C., Libert, C., & Vandenbroucke, R. E. (2016) · Mammalian Genome · doi:10.1007/s00335-016-9647-6 · Cited by 121 · see citing works
Activating secondary metabolism with stress and chemicals
Yoon, V., & Nodwell, J. R. (2013) · Journal of Industrial Microbiology & Biotechnology · doi:10.1007/s10295-013-1387-y · Cited by 116 · see citing works
Therapeutic targeting of the mTOR ‐signalling pathway in cancer: benefits and limitations
Moschetta, M., Reale, A., Marasco, C., Vacca, A., & Carratù, M. R. (2014) · British Journal of Pharmacology · doi:10.1111/bph.12749 · Cited by 116 · see citing works
Enhancing the safety of CAR-T cell therapy: Synthetic genetic switch for spatiotemporal control
Lu, L., Xie, M., Yang, B., Zhao, W., & Cao, J. (2024) · Science Advances · doi:10.1126/sciadv.adj6251 · Cited by 117 · see citing works
The LKB1 tumor suppressor kinase in human disease
Katajisto, P., Vallenius, T., Vaahtomeri, K., Ekman, N., Udd, L., Tiainen, M., & Mäkelä, T. P. (2006) · Biochimica et Biophysica Acta (BBA) - Reviews on Cancer · doi:10.1016/j.bbcan.2006.08.003 · Cited by 107 · see citing works
PIK3CA Exon 20 Mutation is Independently Associated with a Poor Prognosis in Breast Cancer Patients
Lai, Y. L., Mau, B.-L., Cheng, W., Chen, H. M., Chiu, H., & Tzen, C. ‐. (2008) · Annals of Surgical Oncology · doi:10.1245/s10434-007-9751-7 · Cited by 107 · see citing works
The Target of Rapamycin Signalling Pathway in Ageing and Lifespan Regulation
Bjedov, I., & Rallis, C. (2020) · Genes · doi:10.3390/genes11091043 · Cited by 106 · see citing works
Identification of pyrimidine derivatives as hSMG-1 inhibitors
Gopalsamy, A., Bennett, E. M., Shi, M., Zhang, W., Bard, J., & Yu, K. (2012) · Bioorganic & Medicinal Chemistry Letters · doi:10.1016/j.bmcl.2012.08.107 · Cited by 104 · see citing works
Overview of the Indications and Contraindications for Liver TransplantationPreprint
Farkas, S. A., Hackl, C., & Schlitt, H. J. (2014) · Cold Spring Harbor Perspectives in Medicine · doi:10.1101/cshperspect.a015602 · Cited by 101 · see citing works
Ca2+ microdomains in smooth muscle
McCarron, J. G., Chalmers, S., Bradley, K. N., MacMillan, D., & Muir, T. C. (2006) · Cell Calcium · doi:10.1016/j.ceca.2006.08.010 · Cited by 95 · see citing works
Frontier of Epilepsy Research - mTOR signaling pathway
Cho, C. (2011) · Experimental & Molecular Medicine · doi:10.3858/emm.2011.43.5.032 · Cited by 92 · see citing works
Combination Strategies to Improve Targeted Radionuclide Therapy
Chan, T. G., O’Neill, E., Habjan, C., & Cornelissen, B. (2020) · Journal of Nuclear Medicine · doi:10.2967/jnumed.120.248062 · Cited by 91 · see citing works
Distinct Roles for Mammalian Target of Rapamycin Complexes in the Fibroblast Response to Transforming Growth Factor-β
Rahimi, R. A., Andrianifahanana, M., Wilkes, M. C., Edens, M., Kottom, T. J., Blenis, J., & Leof, E. B. (2008) · Cancer Research · doi:10.1158/0008-5472.can-08-2146 · Cited by 91 · see citing works
Insulin and TOR signal in parallel through FOXO and S6K to promote epithelial wound healing
Kakanj, P., Moussian, B., Grönke, S., Bustos, V., Eming, S. A., Partridge, L., & Leptin, M. (2016) · Nature Communications · doi:10.1038/ncomms12972 · Cited by 84 · see citing works
Targeting T Cell Immunometabolism for Cancer Immunotherapy; Understanding the Impact of the Tumor Microenvironment
Mockler, M. B., Conroy, M. J., & Lysaght, J. (2014) · Frontiers in Oncology · doi:10.3389/fonc.2014.00107 · Cited by 87 · see citing works
Autophagy Modulators: Mechanistic Aspects and Drug Delivery Systems
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The two faces of miR-29
Ślusarz, A., & Pulakat, L. (2015) · Journal of Cardiovascular Medicine · doi:10.2459/jcm.0000000000000246 · Cited by 87 · see citing works
Liver transplantation in children with hepatocellular carcinoma Do Milan criteria apply to pediatric patients?
Ismail, H., Broniszczak, D., Kaliciński, P., Markiewicz‐Kijewska, M., Teisseyre, J., Stefanowicz, M., Szymczak, M., Dembowska-Baginska, B. M., Kluge, P., Perek, D., et al. (2009) · Pediatric Transplantation · doi:10.1111/j.1399-3046.2009.01062.x · Cited by 85 · see citing works
From rapalogs to anti-aging formula
Blagosklonny, M. V. (2017) · Oncotarget · doi:10.18632/oncotarget.18033 · Cited by 83 · see citing works
From nature to the laboratory and into the clinic
Nicolaou, K. C., Chen, J. S., & Dalby, S. M. (2008) · Bioorganic & Medicinal Chemistry · doi:10.1016/j.bmc.2008.10.089 · Cited by 81 · see citing works
Sensitive and adaptable pharmacological control of CAR T cells through extracellular receptor dimerization
Leung, W., Gay, J. W., Martin, U., Garrett, T. E., Horton, H. M., Certo, M. T., Blazar, B. R., Morgan, R. A., Gregory, P. D., Jarjour, J., et al. (2019) · JCI Insight · doi:10.1172/jci.insight.124430 · Cited by 79 · see citing works
Disruption of Mammalian Target of Rapamycin Complex 1 in Macrophages Decreases Chemokine Gene Expression and Atherosclerosis
Ai, D., Jiang, H., Westerterp, M., Murphy, A. J., Wang, M., Ganda, A., Abramowicz, S., Welch, C. L., Almazan, F., Zhu, Y., et al. (2014) · Circulation Research · doi:10.1161/circresaha.114.302313 · Cited by 78 · see citing works
FK506 binding proteins: Cellular regulators of intracellular Ca2+ signalling
MacMillan, D. (2013) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2012.12.029 · Cited by 75 · see citing works
mTOR/p70S6K Signal transduction pathway contributes to osteosarcoma progression and patients’ prognosis
Zhou, Q., Deng, Z., Zhu, Y., Long, H., Zhang, S., & Zhao, J. (2009) · Medical Oncology · doi:10.1007/s12032-009-9365-y · Cited by 74 · see citing works
Observations on enhanced port wine stain blanching induced by combined pulsed dye laser and rapamycin administration
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Authors: Law, B. K.
Affiliations: University of Florida (US)
Corresponding author: Law, Brian K.
ORCID: Law, Brian K.
Venue: Critical Reviews in Oncology/Hematology
Publisher: Elsevier BV
Published: 2005-10
Volume: 56
Issue: 1
Pages: 47-60
ISSN: 1040-8428 (ISSN-L)
DOI: 10.1016/j.critrevonc.2004.09.009
OpenAlex: W2764507256
Cited by: 252
References: 256
Citations by year: 2026: 1 · 2025: 12 · 2024: 14 · 2023: 16 · 2022: 14 · 2021: 9 · 2020: 8 · 2019: 18 · 2018: 9 · 2017: 15 · 2016: 9 · 2015: 10 · 2014: 23 · 2013: 16 · 2012: 10
FWCI: 0.97
Type: journal article
Language: en
Open access: closed
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations: Critical Reviews in Oncology/Hematology (publishedVersion)
PubMed (publishedVersion)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Signaling Pathways in Disease
Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
Keywords: rapamycin, mTOR signaling, immunosuppression, anticancer activity, tumor angiogenesis, apoptosis, tumor cell proliferation, cyclosporine, organ transplantation, tumor suppression, PI3K/Akt signaling, TSC1/TSC2, PTEN, LKB1, eIF4E
MeSH terms: Animals, Antineoplastic Agents, Cell Cycle, Drug Synergism, Humans, Immunosuppressive Agents, Neoplasms, Neovascularization, Pathologic, Protein Kinases, Drug Design, Signal Transduction, Molecular Chaperones, Sirolimus, TOR Serine-Threonine Kinases

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Rapamycin: an anti-cancer immunosuppressant?

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