Date of Award


Document Type

Restricted Thesis

Terms of Use

© 2004 Matthew J. Goldstein. All rights reserved. Access to this work is restricted to users within the Swarthmore College network and may only be used for non-commercial, educational, and research purposes. Sharing with users outside of the Swarthmore College network is expressly prohibited. For all other uses, including reproduction and distribution, please contact the copyright holder.

Degree Name

Bachelor of Arts



First Advisor

Kathleen King Siwicki


Statins are drugs known to inhibit 3-hydroxy-3-methylglutaryl coenzyme A (HMG- CoA) reductase, the enzyme of the rate-limiting step in the mevalonate pathway (4, 14). This pathway is responsible for the production of mevalonate, a precursor to both sterol (e.g. cholesterol) as well as non-sterol products critical to cellular survival (21). Statins have also been found to serve as immunodulatory agents in the treatment of certain autoimmune diseases (42) and have further been suggested to affect the proliferation and development of cancers (39). Our studies initially examined the efficacy of statins in treating a transgenic model for T-cell lymphoma developed in the laboratory of Dean Felsher(17). The cell lines were generated from tumors of mice over-expressing RAS, MYC or BCL-2 oncogenes under the control of the Tetracycline expression system. Results showed that atorvastatin induces a reduction in proliferation as well apoptosis specific to cancerous cells only. Both results are markedly similar to the anti-cancer effects generated by oncogene inactivation (17, 23, 24). These effects were reversed by concurrent administration of mevalonate, a downstream product of HMG-CoA reductase, suggesting a mevalonate pathway mediated effect. Molecular analyses showed that atorvastatin treatment disrupts protein farnesylation, a post-translational modification that affects a number of proteins including the cellular growth factor, RAS (l0, 28). A number of downstream targets of RAS were also found to be modified by atorvastatin treatment. These results support a potential role for atorvastatin and other statins as anti-cancer agents, and further implicate the disruption of RAS farnesylation as a possible mediator of the observed effects.