Background & Aims
Chemotherapeutic treatment for breast cancer produces anti-cancer effects but also produces dose-limiting toxicities such as neuropathic pain [1-3]. Inhibition of the primary enzymes that degrade endogenous cannabinoids 2-arachidonoylglycerol (2-AG) and anandamide (AEA) suppress neuropathic nociception in models of chemotherapy-induced peripheral neuropathy (CIPN) and also show anti-cancer properties [4-7]. 2-AG is degraded by the enzyme monoacylglycerol lipase (MGL) whereas AEA is degraded by fatty-acid Amide Hydrolase (FAAH), respectively. A novel CNS-impermeable MGL inhibitor, LEI-515, reversed neuropathic nociception in paclitaxel-treated mice not bearing tumors [8]. In the current studies, we compared a peripheral MGL inhibitor LEI-515, global MGL inhibitor JZL184, and peripheral FAAH inhibitor URB937 for their abilities to suppress development of CIPN and reduce tumor size in a mouse model of breast cancer.
Methods
LEI-515, JZL184, URB937, or vehicle was administered prophylactically before and during administration of chemotherapeutic agent paclitaxel to assess the development of paclitaxel-induced mechanical (assessed by von Frey) and cold (assessed by the acetone test) hypersensitivities in non-tumor bearing mice. Separated groups of female BALBc mice received 4T1 tumor cell line injection into mammary fat pads and were administered LEI-515, JZL184, URB937, or vehicle together with paclitaxel or vehicle with paclitaxel’s vehicle (cremophor) once tumors were palpable. Treatments were administered once daily, whereas paclitaxel or its vehicle were administered every other day. Mechanical and cold hypersensitivities were assessed every 4 days throughout the duration of the study, and tumor sizes were measured daily. Anxiety-like behavior was assessed using the light dark box test. At the terminal endpoint, tumor weight and colonic content weight were assessed.
Results
LEI-515 and URB937 prevented the development of paclitaxel-induced mechanical and cold hypersensitivity in non-tumor bearing mice. JZL184 did not prevent the development of mechanical or cold hypersensitivity; tolerance developed to antinociceptive effects of JZL184. In 4T1 tumor-bearing mice, peripheral MGL inhibitor LEI-515 prevented the development of paclitaxel-induced mechanical and cold hypersensitivity and reduced tumor size compared to paclitaxel alone. Global MGL inhibitor JZL184 reduced tumor size compared to paclitaxel alone but did not prevent mechanical or cold hypersensitivity. Peripheral FAAH inhibitor URB937 attenuated mechanical and cold hypersensitivity but did not reduce tumor size compared to paclitaxel alone. Paclitaxel-treated mice that received LEI-515 showed reduced tumor weights. Colonic weights of all paclitaxel groups increased.
Conclusions
The combination of LEI-515 with paclitaxel produced a greater reduction in tumor size than paclitaxel alone, while also suppressing mechanical and cold hypersensitivities associated with CIPN. Inhibition of MGL produces anti-cancer properties. The peripherally-restricted MGL inhibitor exhibited more promise for suppressing development of CIPN compared to the global MGL inhibitor JZL184. Tolerance developed to anti-allodynic effects of JZL184 but not LEI-515. The peripherally restricted FAAH inhibitor URB937 is a promising option for chemotherapy-induced neuropathic pain, as it prevented mechanical and cold hypersensitivities from fully developing without impeding anti-tumor efficacy of paclitaxel. None of the pharmacological treatments reliably altered anxiety-like behavior in tumor-bearing mice. Overall, peripheral MGL and FAAH inhibition hold therapeutic potential for suppressing development of CIPN in breast cancer patients.
References
1. Michaud, L. B., Valero, V., & Hortobagyi, G. (2000). Risks and benefits of taxanes in breast and ovarian cancer. Drug safety, 23, 401-428.
2. Rowinsky, E. K., & Donehower, R. C. (1995). Paclitaxel (taxol). New England journal of medicine, 332(15), 1004-1014.
3. Klein I, Lehmann HC. Pathomechanisms of Paclitaxel-Induced Peripheral Neuropathy. Toxics. 2021 Sep 22;9(10):229. doi: 10.3390/toxics9100229. PMID: 34678925; PMCID: PMC8540213.
4. Curry, Z. A., Wilkerson, J. L., Bagdas, D., Kyte, S. L., Patel, N., Donvito, G., … & Lichtman, A. H. (2018). Monoacylglycerol lipase inhibitors reverse paclitaxel-induced nociceptive behavior and proinflammatory markers in a mouse model of chemotherapy-induced neuropathy. Journal of Pharmacology and Experimental Therapeutics, 366(1), 169-183.
5. Slivicki, R. A., Xu, Z., Kulkarni, P. M., Pertwee, R. G., Mackie, K., Thakur, G. A., & Hohmann, A. G. (2018). Positive allosteric modulation of cannabinoid receptor type 1 suppresses pathological pain without producing tolerance or dependence. Biological psychiatry, 84(10), 722-733.
6. Tripathy, M., Bui, A., Henderson, J., Sun, J., Woods, C. R., Somani, S., … & Mohan, C. (2023). FAAH inhibition ameliorates breast cancer in a murine model. Oncotarget, 14, 910.
7. Slivicki, R. A., Xu, Z., Mali, S. S., & Hohmann, A. G. (2019). Brain permeant and impermeant inhibitors of fatty-acid amide hydrolase suppress the development and maintenance of paclitaxel-induced neuropathic pain without producing tolerance or physical dependence in vivo and synergize with paclitaxel to reduce tumor cell line viability in vitro. Pharmacological Research, 142, 267-282.
8. Jiang, M., Huizenga, M. C., Wirt, J. L., Paloczi, J., Amedi, A., van den Berg, R. J., … & van der Stelt, M. (2023). A monoacylglycerol lipase inhibitor showing therapeutic efficacy in mice without central side effects or dependence. Nature Communications, 14(1), 8039.
9. Bray, F., Laversanne, M., Weiderpass, E., & Soerjomataram, I. (2021). The ever?increasing importance of cancer as a leading cause of premature death worldwide. Cancer, 127(16), 3029-3030.
10. Ferlay, J., Colombet, M., Soerjomataram, I., Parkin, D. M., Piñeros, M., Znaor, A., & Bray, F. (2021). Cancer statistics for the year 2020: An overview. International journal of cancer, 149(4), 778-789.
Presenting Author
Jonah Wirt
Poster Authors
Jonah Wirt
BSc
Indiana University Bloomington
Lead Author
Emily Fender-Sizemore
BS
Indiana University Bloomington
Lead Author
Mirjam Huizenga
BS
Leiden University & Oncode Institute, Netherlands
Lead Author
Mario van der Stelt
PhD
Leiden University & Oncode Institute, Netherlands
Lead Author
Topics
- Models: Chronic Pain - Neuropathic