Rapamycin: An anti-cancer immunosuppressant?

https://doi.org/10.1016/j.critrevonc.2004.09.009Get rights and content

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.

Introduction

Rapamycin is perhaps best known as a potent immunosuppressive agent. It is unclear from this vantage point what utility rapamycin might have as an anti-cancer agent. This perspective however stems from the historical development of rapamycin use rather than the intrinsic nature of rapamycin action. The aim of this review is to rationalize how rapamycin is able to act both as an immunosuppressive agent and an anti-cancer agent.

Rapamycin was first identified as an anti-fungal agent produced by the bacterium Streptomyces hygroscopicus [1], [2] and was subsequently demonstrated to be a potent immunosuppressive agent [3], [4], [5], [6]. The target of rapamycin (TOR) was identified in a screen of yeast mutants able to proliferate in the presence of rapamycin [7]. A mammalian protein homologous to TOR (mTOR) was isolated later based on its ability to bind the FK506 binding protein FKBP12 [8], [9], [10]. TOR bound to FKBP12 in the presence of rapamycin, but not in the presence of the related immunosuppressant bacterial macrolide FK506. mTOR is a 289 kDa protein that is evolutionarily related to lipid kinases, but exhibits protein serine/threonine kinase activity (reviewed in [11]).

Section snippets

TOR and mTOR regulate cell proliferation in response to nutrient availability

Cell proliferation must be regulated such that cell division occurs only when adequate levels of all necessary nutrients are available. However, despite detailed knowledge of how cells respond to growth factors, relatively little is known concerning how cells respond to changes in nutrient levels. In budding yeast, the TOR proteins mediate responses to levels of nutrients such as nitrogen [12], [13]. In mammals, mTOR integrates signals and mediates biological responses to growth factors and

Rapamycin as an immunosuppressant

Shortly after it was first described as an anti-fungal antibiotic [1], [2] rapamycin was demonstrated to have immunosuppressant properties as indicated by its ability to inhibit experimental allergic encephalomyelitis, adjuvant arthritis, and the humoral (IgE) immune response [127]. Several years later, rapamycin was shown to inhibit tumor growth in xenograft models [128], an observation seemingly inconsistent with rapamycin acting as an immunosuppressant. The observation that rapamycin shares

The mTOR signaling pathway is activated in cancers

A hallmark of human cancer is deregulation of the cell cycle [146]. Consistent with the notion that the mTOR pathway is a key regulator of cell proliferation, several upstream activators and downstream effectors of mTOR are deregulated in cancers (Table 1). The two most well studied mTOR effectors are p70s6k and 4EBP1. p70s6k is overexpressed in breast cancers and is constitutively activated in several types of cancers [121], [147], [148]. Significantly, p70s6k overexpression correlates with

The mTOR pathway as a target of multiple existing anti-cancer agents

As discussed above the PI3 kinase pathway and mTOR signaling are inextricably intertwined. To complicate matters, presumed PI3K inhibitors such as wortmannin and LY294004 also inhibit mTOR [31]. Thus, the anti-proliferative, anti-cancer effects of PI3K inhibitors may be partially attributable to mTOR inactivation.

We have shown that the aspirin metabolite salicylate inhibits p70s6k activation and induces many of the same biochemical cell cycle responses as rapamycin [88]. This suggests that some

Conclusions

Rapamycin targets an evolutionarily conserved nutrient-responsive cell cycle regulatory pathway. Thus, the potent cytostatic nature of rapamycin stems from its ability to trigger a nutrient deprivation-like response. The growth inhibitory properties of rapamycin prompted researchers to explore the potential anti-cancer properties of rapamycin. It is clear from the discussion above that rapamycin is both a potent immunosuppressant and a promising anti-cancer agent. The anti-tumor efficacy of

Reviewers

Dr. Iduna Fichtner, Max-Delbrück-Centrum for Molecular Medicine, Experimental Pharmacology, Robert-Rössle-Str. 10, D-13125 Berlin-Buch, Germany.

Prof. Jaap Verweij, Department of Oncology, Erasmus University Medical Center, Postbus 5201 (Groene Hilledijk 301), NL-3008AE Rotterdam, The Netherlands.

Joon-Ho Sheen, Ph.D., Sabatini Lab, Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, MA 02142-1479, USA.

Robert T. Abraham, Ph.D., Professor and Director, Cancer Research

Brian Law obtained his Ph.D. in biochemistry in 1996 from Purdue University, West Lafayette, IN, USA. He is currently an assistant professor in the Department of Pharmacology and Therapeutics at the University of Florida, Gainesville, FL, USA.

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    Brian Law obtained his Ph.D. in biochemistry in 1996 from Purdue University, West Lafayette, IN, USA. He is currently an assistant professor in the Department of Pharmacology and Therapeutics at the University of Florida, Gainesville, FL, USA.

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