TEMPOL for Cancer– Why Treat Fibrocystic Change?
Jan 11, 2015
Peter H Proctor, PhD, MD
TEMPOL is a small-molecule “SOD-mimetic”, effective in a variety of experimental cancer models, both in vivo and in vitro. Tracing back to the Warburg effect, its putative mechanism of action is destruction of reactive oxygen species (ROS). These drive the cancer process by both induction of genetic instability and by their action on cellular growth and replication. Toxicity is very low, e.g., TEMPOL extends lifespan in rodents. Review: See Wilcox, ref 1.
Defined drug targets include important cell-growth and check factors*. E.g., with respect to BRCA1, “Pharmacological disruption of CtBP1 binding to Brca1 promoter by the antioxidant Tempol, relieved CtBP1-mediated repression of Brca1..”(2). Most importantly, by acting on cells in the local microenviornment, TEMPOL is “synthetically-lethal” to BRCA1-/- breast cancer and phenotypically-similar cells in vitro (3). This is a Holy Grail in cancer treatment.
That is, TEMPOL treats cancers in which ROS production in the local microenviornment is important. This is in accord with the anticancer action of ectopic bovine liver SOD1 itself, which does not penetrate inside of cells. This anticancer action has been known since the 1970’s (see below).
Most importantly, unexpected efficacy in fibrocystic change (FC) implies that microenviornmental ROS are also important in benign breast disease. That is, fibrocystic change may be a surrogate endpoint for breast cancer treatment, as well as for treatment of other cancers with a microenviornmental component.
Moreover, unlike cancer, fibrocystic change is rarely-treated. Thus, trials are potentially clean, fast, and the number of potential research subjects is much greater. TEMPOL is also complimentary to other treatments. Examples include prevention of the evolution of drug-resistant clones and amelioration of the toxicity of cancer chemotherapy. Arguably, the patent situation is also better, with fresh patents and essentially no pesky prior art or competing or expired patents.
For example, FDA researchers report that, in addition to inhibiting cancer growth, a targeted form enhances the effectiveness and cuts the toxicity of doxorubicin in syngeneic breast cancer (4) . TEMPOL also works in transplanted human melanoma (5), as well as other cancers such as glioma. Importantly, “… effects of Tempol on AR function were accompanied by significant in vitro and in vivo reduction in castration-resistant prostate cancer (CRPC) survival and growth”(6). Finally, an NCI solicitation** states that “Therefore, TEMPOL can potentially be developed into a cancer drug to treat patients with elevated HIF-2α…” And so forth.
In a reprise of our work with SOD1, TEMPOL also protects against cis-platinum toxicity (7). According to the NCI group, TEMPOL is antimutagenic, particularly in cancer cells. Thus, TEMPOL may delay emergence of treatment-resistant clones. It also inhibits the action of mGluRs, “metabotropic glutamate receptors”. This action is potentially important in (e.g.) glioma, melanoma, and breast cancer treatment.
Background: In the 1970’s, we at MD Anderson (8) and others (9) at the U of Iowa discovered that an ectopic superoxide dismutase (“SOD1”) inhibits cancer growth in vivo. Most significantly, the Iowa researchers also reported dropout of mitochondrial SOD in many cancers.
Because SOD1 does not penetrate well into cells, arguably it acts in the microenvironment. This is in accord with later work with the analogous SOD-mimetic TEMPOL(3). Interestingly, in a straight-up comparison, SOD1 is as effective an anticancer agent as cis-platinum in our hamster leiomyoscarcoma model(10).
Similarly, we showed that oxidative stress figures in the in vivo toxicity and perhaps action of cis-platinum, bleomycin, and doxorubicin (8,10). We also originally proposed that reactive oxygen species are cellular messengers, part of “redox signaling”. Since then. others have greatly expanded this work, resulting in several thousand publications.
More recently, NCI researchers report the similar anticancer and cancer-preventive action of the SOD-mimetic TEMPOL. NCI-sponsored clinical trials for radiation alopecia and dermatitis overlap our patents (e.g.,“Topical TEMPO”, US#5352442). Currently, the NCI has topical TEMPOL in human trials as a radioprotectant and chemoprotectant and is soliciting collaborative ventures for cancer treatment**. Similarly, the FDA has an active program on a TEMPOL-derivative in the treatment of breast cancer (3).
I am currently patenting related applications for which there is no “prior art”. For example, I just received US patent # US8778969 for the treatment of fibrocystic change of breast and have other patents pending for other indications. While most fibrocystic change is not associated with an increased incidence of breast cancer, this is doubled with a strong family history of breast cancer. Proliferative changes or atypia likewise increase the probability of breast cancer roughly four-fold. Arguably, reactive species produced in the microenvironment drive both fibrocystic change and breast cancer, making this work generally-applicable to other types of cancer.
*TEMPOL targets: BRCA1, CtBP1, p53, PARP, HIF-1α, HIF-2α, VEGF, IL-6, BARD1, RAD51, uPAR, mGluRs
** NIH solicitation: “Tempol: A Commercially Available Nitroxide as Cancer Therapeutics” “Therefore, TEMPOL can potentially be developed into a cancer drug to treat patients with elevated HIF-2alpha, whether due to compromised VHL function or not. “ http://www.ott.nih.gov/technology/e-133-20090.
Press Release: http://www.sfrbm.org/sections/tempolrelease
Case report: “TEMPOL-H for Fibrocystic Breast Disease”– http://www.drproctor.com/nitroxide/tempolabstract.htm .
1.Wilcox CS., Effects of tempol and redox-cycling nitroxides in models of oxidative stress. Pharmacol Ther. 2010 May;126(2):119-45. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2854323/
- Deng Y(1), et al, “Redox-dependent Brca1 transcriptional regulation by an NADH-sensor CtBP1.” Oncogene. 2010 Dec 16;29(50):6603-8. doi: 10.1038/onc.2010.406. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3081720/
- Martinez-Outschoorn UE1, et al, “BRCA1 mutations drive oxidative stress and glycolysis in the tumor microenvironment: implications for breast cancer prevention with antioxidant therapies.” Cell Cycle. 2012 Dec 1;11(23):4402-13. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3552923/
- Dickey JS et al, Mito-tempol and dexrazoxane exhibit cardioprotective and chemotherapeutic effects through specific protein oxidation and autophagy in a syngeneic breast tumor preclinical model.PLoS One. 2013 Aug 5;8(8):e70575. doi: 10.1371/journal.pone.0070575. http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0070575
- Nazarewicz RR et al, Does scavenging of mitochondrial superoxide attenuate cancer prosurvival signaling pathways? Antioxid Redox Signal. 2013 Aug 1;19(4):344-9. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3700017/.
- Thomas R1, Sharifi N., “SOD Mimetics: A Novel Class of Androgen Receptor Inhibitors That Suppresses Castration-Resistant Growth of Prostate Cancer” Mol Cancer Ther. 2012 Jan;11(1):87-97. doi: 10.1158/1535-7163.MCT-11-0540, http://mct.aacrjournals.org/content/11/1/87.long
- Lamiaa A. et al “Tempol, a Superoxide Dismutase Mimetic Agent, Ameliorates Cisplatin-Induced Nephrotoxicity through Alleviation of Mitochondrial Dysfunction in Mice” October 01, 2014, DOI: 10.1371/journal.pone.0108889 http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0108889
- McGinness JE, Proctor PH, et al, Amelioration of cis-platinum nephrotoxicity by orgotein (superoxide dismutase).Physiol Chem Phys. 1978;10(3):267-77.
- Oberly et al.”The Use of Superoxide Dismutase in the Treatment of Cancer,”, in “Pathology of Oxygen”, Academic Press (1982) p201
- McGinness, JE, Proctor, PH et al, “An in vivo Enzymatic Probe for Superoxide and Peroxide Production by Chemotherapeutic Agents”, in “Pathology of Oxygen”, Academic Press (1982) p191.