Repurposing Orlistat: Anti-Cancer Mechanisms and Potential in Therapeutics

Orlistat, developed initially and FDA-approved as an anti-obesity drug, inhibits pancreatic and gastric lipases, thereby reducing dietary fat absorption. However, emerging research over the past two decades has positioned Orlistat as a potent anti-cancer agent. Its anti-tumor effects largely stem from its role as an inhibitor of fatty acid synthase (FASN), an enzyme essential for lipid metabolism that is often upregulated in cancer cells to support rapid proliferation, survival, and metastasis. Cancer cells rely heavily on de novo lipogenesis, driven by FASN, to meet their high energy demands and facilitate membrane synthesis. By targeting this pathway, Orlistat disrupts lipid metabolism and induces cytotoxic effects in various cancer models.

Mechanisms of Action in Cancer Therapy

Orlistat’s anti-cancer effects are multi-faceted, involving lipid metabolism disruption, apoptosis induction, ferroptosis-like cell death, and antiangiogenic activity. Below is a breakdown of these mechanisms based on the recent studies:

1. FASN Inhibition and Apoptosis Induction

Orlistat’s primary anti-cancer mechanism involves the inhibition of FASN. By blocking FASN, Orlistat effectively cuts off the cancer cell’s supply of fatty acids essential for cell membrane synthesis and energy production. This disruption forces cancer cells into metabolic stress, leading to cell cycle arrest and apoptosis. Studies across multiple cancer types, including breast, prostate, lung, and pancreatic cancers, have demonstrated that Orlistat can significantly reduce tumor cell proliferation and induce apoptosis by modulating the expression of apoptotic proteins such as Bax, Bcl-2, and caspase-3.

Orlistat induces significant cytotoxicity in breast cancer cells and enhances apoptotic markers without affecting normal breast cells, highlighting its selective toxicity. This selectivity positions Orlistat as a potentially safe and effective treatment option. Similarly, in pancreatic cancer, Orlistat reduces proliferation and promotes apoptosis by targeting FASN, interrupting the metabolic pathways essential for tumor growth.

2. Ferroptosis and Ferroptosis-Like Cell Death

A novel discovery regarding Orlistat’s mechanism is its induction of ferroptosis-like cell death, particularly noted in lung cancer cells. Ferroptosis is an iron-dependent form of cell death characterized by lipid peroxidation. Orlistat achieves this by downregulating GPX4, a critical enzyme that protects against lipid peroxidation, and increasing reactive oxygen species (ROS) levels. The accumulation of ROS leads to oxidative damage and, ultimately, cell death. This ferroptotic pathway adds a layer of lethality to Orlistat’s anti-tumor effects, making it particularly effective against cancers with high oxidative stress responses.

3. Antiangiogenic Effects

Orlistat has shown promising antiangiogenic properties by inhibiting endothelial cell proliferation, an essential step in tumor angiogenesis. Inhibition of FASN in endothelial cells by Orlistat blocks fatty acid synthesis, which is critical for new blood vessel formation. Additionally, Orlistat downregulates the expression of VEGFR2, a receptor essential for vascular endothelial growth factor (VEGF) signaling in angiogenesis. This antiangiogenic effect disrupts the tumor’s ability to establish a blood supply, thereby limiting its growth and metastatic potential. The antiangiogenic effects have been observed in breast and colorectal cancer models, emphasizing Orlistat’s potential in targeting vascular-dependent tumors.

4. Anti-Inflammatory Effects and Immune Modulation

In inflammation-driven cancers, such as colitis-associated colon cancer, Orlistat reduces tumor-promoting inflammation by inhibiting the NF-κB and STAT3 pathways. These pathways regulate pro-inflammatory cytokine production and cell survival in the tumor microenvironment. By blocking these pathways, Orlistat decreases chronic inflammation, reducing the risk of progression from chronic inflammatory conditions to cancer. This is particularly relevant in cancers influenced by the Western diet, where chronic inflammation contributes to tumor initiation and growth.

Orlistat’s immune-modulatory effects extend to its role in promoting the differentiation and activation of macrophages, critical players in the anti-tumor immune response. In T-cell lymphoma models, Orlistat enhances myelopoiesis and promotes the differentiation of bone marrow cells into M1 macrophages, a tumoricidal phenotype. This boosts the body’s natural immune response against tumors, making Orlistat a promising agent for immunomodulatory therapy.

5. Metabolic Reprogramming and Combination with Metabolic Inhibitors

Cancer cells often adapt to metabolic stress by shifting between glycolysis and lipid metabolism. In gastric cancer models, Orlistat has shown increased efficacy when combined with PGM1 knockdown, which limits glycolytic activity. Under glucose-deprived conditions, the knockdown of PGM1 alongside Orlistat treatment prevents cancer cells from compensating with lipid metabolism, enhancing Orlistat’s anti-cancer effects. This combination targets cancer cells' metabolic flexibility, exploiting their dependency on glucose and fatty acid pathways to sustain growth.

6. Delay in Hepatocarcinogenesis

Studies have shown that Orlistat delays the onset and progression of hepatocellular carcinoma (HCC) in animal models with hepatic co-activation of AKT and c-Met, common pathways in liver cancer. Orlistat impairs AKT/SREBP1/FASN signaling, reducing lipogenesis and cell proliferation. This mechanism suggests that Orlistat could be beneficial in managing HCC, especially in patients with metabolic dysfunctions that heighten their risk for liver cancer.

Mechanisms of Orlistat’s Anti-Cancer Activity

Orlistat’s multi-targeted approach offers a promising route for treating various types of cancer, particularly those reliant on lipid metabolism. Its ability to induce selective cytotoxicity, modulate immune responses, and disrupt cancer metabolism highlights its versatility as an anti-cancer agent. However, challenges remain, primarily related to its bioavailability and off-target effects.

Studies have demonstrated Orlistat’s efficacy in in vitro and in vivo models, but its low systemic bioavailability when administered orally limits its effectiveness in specific cancers. 

Another consideration is patient selection. Orlistat may be particularly effective for patients with cancers characterized by metabolic dysregulation, such as those with obesity-driven cancers or metabolic syndrome. Further studies are needed to identify specific biomarkers that can predict response to Orlistat and guide its clinical use.

Orlistat, though developed initially for obesity management, holds substantial promise in oncology due to its multi-faceted mechanisms that target cancer cell metabolism, induce cell death, and modulate immune responses. Its efficacy across various cancers, including breast, lung, pancreatic, colon, and liver, underscores its potential as a repurposed therapeutic. 

References

Kant, Shiva & Kumar, Ajay & Singh, Sukh. (2013). Myelopoietic Efficacy of Orlistat in Murine Hosts Bearing T Cell Lymphoma: Implication in Macrophage Differentiation and Activation. PloS one. 8. e82396. 10.1371/journal.pone.0082396. 

Kant, Shiva & Kumar, Ajay & Singh, Sukh. (2012). Fatty acid synthase inhibitor orlistat induces apoptosis in T cell lymphoma: Role of cell survival regulatory molecules. Biochimica et biophysica acta. 1820. 1764-73. 10.1016/j.bbagen.2012.07.010. 

Schcolnik-Cabrera, Alejandro & Chavez, Alma & Gomez, Guadalupe & Taja, Lucia & Cardenas-Barcenas, Rocio & Trejo-Becerril, Catalina & Perez-Cardenas, Enrique & Gonzalez-Fierro, Aurora & Duenas-Gonzalez, Alfonso. (2018). Orlistat as a FASN inhibitor and multitargeted agent for cancer therapy. Expert Opinion on Investigational Drugs. 27. 10.1080/13543784.2018.1471132. 

Dowling, Shawn & Cox, James & Cenedella, Richard. (2009). Inhibition of Fatty Acid Synthase by Orlistat Accelerates Gastric Tumor Cell Apoptosis in Culture and Increases Survival Rates in Gastric Tumor Bearing Mice In Vivo. Lipids. 44. 489-98. 10.1007/s11745-009-3298-2. 

Sokolowska, Ewa & Presler, Malgorzata & Goyke, Elzbieta & Milczarek, Ryszard & Swierczynski, Julian & Sledzinski, Tomasz. (2017). Orlistat Reduces Proliferation and Enhances Apoptosis in Human Pancreatic Cancer Cells (PANC-1). Anticancer research. 37. 6321-6327. 10.21873/anticanres.12083. 

Jovankić, Jovana & Nikodijević, Danijela & Milutinović, Milena & Nikezic, Aleksandra & Kojić, Vesna & Cvetković, Aleksandar & Cvetkovic, Danijela. (2022). Potential of Orlistat to induce apoptotic and antiangiogenic effects as well as inhibition of fatty acid synthesis in breast cancer cells. European Journal of Pharmacology. 939. 175456. 10.1016/j.ejphar.2022.175456. 

Elmasry, Thanaa & El-Nagar, Maysa & Oriquat, Ghaleb & Alotaibi, Badriyah & Saad, Hebatallah M. & El Zahby, Enas & Ibrahim, Hanaa. (2024). Therapeutic efficiency of Tamoxifen/Orlistat nanocrystals against solid ehrlich carcinoma via targeting TXNIP/HIF1-α/MMP-9/P27 and BAX/ Bcl2/P53 signaling pathways. Biomedicine & Pharmacotherapy. 180. 10.1016/j.biopha.2024.117429. 

Zhang, Cong & Sheng, Lei & Yuan, Ming & Hu, Junjie & Meng, Yan & Wu, Yong & Chen, Liang & Yu, Huifan & Li, Shan & Zheng, Guohua & Qiu, Zhenpeng. (2020). Orlistat delays hepatocarcinogenesis in mice with hepatic co-activation of AKT and c-Met. Toxicology and Applied Pharmacology. 392. 114918. 10.1016/j.taap.2020.114918. 

Xu, Guangxu & Zhao, Ziyi & Wysham, Weiya & Roque, Dario & Fang, Ziwei & Sun, Wenchuan & Yin, Yajie & Deng, Boer & Shen, Xiaochang & Bae-Jump, Victoria. (2023). Orlistat exerts anti-obesity and anti-tumorigenic effects in a transgenic mouse model of endometrial cancer. Frontiers in Oncology. 13. 10.3389/fonc.2023.1219923. 

Cervantes Madrid, Diana & Gomez, Guadalupe & Gonzalez‑Fierro, Aurora & Perez-Cardenas, Enrique & Taja, Lucia & Trejo-Becerril, Catalina & Duenas-Gonzalez, Alfonso. (2017). Feasibility and antitumor efficacy in vivo, of simultaneously targeting glycolysis, glutaminolysis and fatty acid synthesis using lonidamine, 6-diazo-5-oxo-L-norleucine and orlistat in colon cancer. Oncology Letters. 13. 10.3892/ol.2017.5615. 

Zhou, Wenjing & Zhang, Jing & Yan, Mingkun & Wu, Jin & Lian, Shuo & Sun, Kang & Li, Baiqing & Ma, Jia & Xia, Jun & Lian, Chaoqun. (2021). Orlistat induces ferroptosis-like cell death of lung cancer cells. Frontiers of Medicine. 15. 10.1007/s11684-020-0804-7. 

Ye, Mujie & Lu, Feiyu & Chen, Jinhao & Yu, Ping & Xu, Yanling & He, Na & Hu, Chunhua & Zhong, Yuan & Yan, Lijun & Gu, Danyang & Xu, Lin & Bai, Jianan & Tian, Ye & Tang, Qiyun. (2023). Orlistat Induces Ferroptosis in Pancreatic Neuroendocrine Tumors by Inactivating the MAPK Pathway. Journal of Cancer. 14. 1458-1469. 10.7150/jca.83118. 

Mojjarad, Behnam & Pazhang, Yaghub. (2020). Orlistatand and Rosuvastatin Suppressed Proliferation of K562 Human Myelogenous Leukemia Cell Line through AMPK/Akt/c-Myc Signaling. 10.21203/rs.3.rs-18746/v2.