Nelfinavir, a new anti-cancer drug with pleiotropic effects and many paths to autophagy
- PMID: 18000394
- DOI: 10.4161/auto.5224
Nelfinavir, a new anti-cancer drug with pleiotropic effects and many paths to autophagy
Abstract
The development of cancer drugs is slow and costly. One approach to accelerate the availability of new drugs is to reposition drugs approved for other indications as anti-cancer agents. HIV protease inhibitors (HIV PIs) are useful in treating HIV infection and cause toxicities in humans that are similar to those observed when the kinase Akt, a target for cancer therapy, is inhibited. To test whether HIV PIs inhibited Akt and cancer cell proliferation, we screened 6 HIV PIs and found that three, ritonavir, saquinavir and nelfinavir, inhibit the growth of over 60 cancer cell lines derived from 9 different tumor types; Nelfinavir is the most potent. Nelfinavir causes caspase-dependent apoptosis and non-apoptotic death, as well as endoplasmic reticulum (ER) stress and autophagy. Nelfinavir blocks growth factor receptor activation and decreases growth factor-induced and endogenous Akt signaling. In vivo, nelfinavir inhibits tumor growth and upregulates markers of ER stress, autophagy and apoptosis. Nelfinavir is currently being tested in cancer patients in Phase I clinical trials where biomarkers will be assessed. Current studies are focused on measuring autophagy in clinical specimens and identifying combination strategies that will exploit the induction of autophagy and increase the effectiveness of nelfinavir.
Similar articles
-
Nelfinavir, A lead HIV protease inhibitor, is a broad-spectrum, anticancer agent that induces endoplasmic reticulum stress, autophagy, and apoptosis in vitro and in vivo.Clin Cancer Res. 2007 Sep 1;13(17):5183-94. doi: 10.1158/1078-0432.CCR-07-0161. Clin Cancer Res. 2007. PMID: 17785575
-
The HIV protease inhibitor nelfinavir down-regulates RET signaling and induces apoptosis in medullary thyroid cancer cells.J Clin Endocrinol Metab. 2014 May;99(5):E734-45. doi: 10.1210/jc.2013-3369. Epub 2014 Jan 31. J Clin Endocrinol Metab. 2014. PMID: 24483157
-
Tamoxifen enhances the cytotoxic effects of nelfinavir in breast cancer cells.Breast Cancer Res. 2010;12(4):R45. doi: 10.1186/bcr2602. Epub 2010 Jul 1. Breast Cancer Res. 2010. PMID: 20594311 Free PMC article.
-
HIV-1 protease inhibitors. A review for clinicians.JAMA. 1997 Jan 8;277(2):145-53. JAMA. 1997. PMID: 8990341 Review.
-
Antitumorigenic action of nelfinavir: Effects on multiple myeloma and hematologic malignancies (Review).Oncol Rep. 2020 Jun;43(6):1729-1736. doi: 10.3892/or.2020.7562. Epub 2020 Mar 26. Oncol Rep. 2020. PMID: 32236596 Review.
Cited by
-
Autophagy controls p38 activation to promote cell survival under genotoxic stress.J Biol Chem. 2013 Jan 18;288(3):1603-11. doi: 10.1074/jbc.M112.415224. Epub 2012 Dec 4. J Biol Chem. 2013. PMID: 23212914 Free PMC article.
-
Targeting the hallmarks of cancer with therapy-induced endoplasmic reticulum (ER) stress.Mol Cell Oncol. 2014 Dec 1;2(1):e975089. doi: 10.4161/23723556.2014.975089. eCollection 2015 Jan-Mar. Mol Cell Oncol. 2014. PMID: 27308392 Free PMC article. Review.
-
Nelfinavir restricts A549 cell growth by inhibiting STAT3 signaling.J Int Med Res. 2021 Jun;49(6):3000605211014989. doi: 10.1177/03000605211014989. J Int Med Res. 2021. PMID: 34167351 Free PMC article.
-
The HIV-1 protease inhibitor nelfinavir activates PP2 and inhibits MAPK signaling in macrophages: a pathway to reduce inflammation.J Leukoc Biol. 2012 Oct;92(4):795-805. doi: 10.1189/jlb.0911447. Epub 2012 Jul 11. J Leukoc Biol. 2012. PMID: 22786868 Free PMC article.
-
Andrographolide Analogue Induces Apoptosis and Autophagy Mediated Cell Death in U937 Cells by Inhibition of PI3K/Akt/mTOR Pathway.PLoS One. 2015 Oct 5;10(10):e0139657. doi: 10.1371/journal.pone.0139657. eCollection 2015. PLoS One. 2015. PMID: 26436418 Free PMC article.
MeSH terms
Substances
LinkOut - more resources
Full Text Sources
