An important conclusion:
After all the literature I read on ACC, I conclude that hormone producing ACC tumors are highly susceptible to hormone inhibitors. More specifically, it seems that most of the drugs that are inhibiting hormone production can lead to the adrenal cancer cell death when the ACC is functional and producing hormones such as cortisol or testosterone.
Here is a recent publication that comes to further support my conclusion: Antisecretive and Antitumor Activity of Abiraterone Acetate in Human Adrenocortical Cancer: A Preclinical Study http://press.endocrine.org/doi/pdf/10.1210/jc.2016-2414 Of note is that the IC50 value of 63 nM fell within the range of the reported Cmax plasma drug concentrations at steady-state when AA was administered to CRPC patients at a daily dose of 1000 mg (226 178 ng/ml; corresponding to a range from 19 to 157 nM).
Note that in the above paper, the antitumor effect of AA was attributed to PgR signaling, via negative modulation of the Wnt/-catenin pathway, could contribute to AA inhibition of cell viability in ACC. Although this is a different mechanism that apparently doesn’t have anything to do with the impact of AA on hormone production, I personally believe that it should be somehow connected with that even if not apparent from the experiments. In the end the used AA not because they expected to have anti cancer effects but to study the hormone production inhibition in ACC.
Beyond this, there are many more publications indicating anti-ACC activity of the hormone inhibitors such as Etomidate, Ketokonazole and off course Mitotane and the new ATR-101.
Recent (end 2015) study showing that Mitotane is not associated with improved recurrence-free or overall survival in ACC cases
Background: Current treatment guidelines recommend adjuvant mitotane after resection of adrenocortical carcinoma with high-risk features (tumor rupture, positive margins, positive lymph nodes, high grade, elevated mitotic index, and advanced stage). Limited data exist on the outcomes associated with these practice guidelines.
Conclusion of the study: When accounting for stage and adverse tumor and treatment-related factors, adjuvant mitotane after resection of adrenocortical carcinoma is not associated with improved recurrence-free or overall survival. Current guidelines should be revisited; prospective trials are needed. http://www.journalacs.org/article/S1072-7515(15)01804-9/abstract
Functional ACC producing DHEA/Testosterone may not respond to Doxorubicin
The typical chemo combination used to treat ACC is Etoposide, doxorubicin and cisplatin plus mitotane (EDP-mitotane). However, I recently find out that pentose phosphate pathway inhibition may lead to ineffectivness of doxorubicin:
“Anthracyclines are a class of antibiotics used in cancer therapy, and the most commonly used member of this class is adriamycin, also known as doxorubicin. Anthracyclines are metabolized by cytochrome p450 reductase to produce free radicals, which induce cytotoxicity72. Because NADPH is a cofactor that is required for this activity of cytochrome p450, the high levels of NADPH generated by the PPP may sensitize cancer cells to doxorubicin. Consistently, adriamycin/doxorubicin-resistant MCF-7 cells display reduced G6PDH and PPP activity compared to sensitive cells66.” https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4329227/
This piece of info is important since glucose-6-phosphate dehydrogenase, the rate-limiting enzyme in the pentose phosphate pathway can be inhibited by DHEA https://www.ncbi.nlm.nih.gov/pubmed/24036000
And DHEA is an androgen precursor that is often elevated in functional ACC (Ref.).
Therefore, in many but not all ACCs, DHEA is elevated and in this case there is a good chance for NO response to doxorubicin.
Inhibition of DHEA levels to prepare for Doxorubicin treatment may make sense. However, that may be difficult to achieve since most of hormone production inhibition, such as Ketokonazole, are inhibitors of cytochrome p450 (Ref.) which is also required for Doxorubicin metabolism, as discussed above.
According to the above, cytochrome p450 inhibitors such as Ketokonazole (typically used in functional ACCs) may reduce Doxorubicin effectiveness.
Below are drugs/supplements that may help against ACC or against hormone production related to the functional ACC:
Good report to have a feeling on the drugs relevant to ACC and currenly in clinical trials: Adrenocortical Carcinoma Therapeutic Assessment Pipeline Review H1 2015 Market Research Report Drugs profiles discussed in this report includes ATR-101, avelumab, axitinib, MP-110, NTX-010, Small Molecules to Antagonize Steroidogenic Factor-1, TKM-PLK1
Bellow are various drugs that I consider relevant to ACC:
HDAC inhibitors making some ACCs less aggressive:
The human adrenocortical carcinoma SW13 cell line has two subtypes that are phenotypically distinct. The SW13- subtype is highly proliferative and epithelial-like, while the SW13+ subtype is slow growing, motile, and mesenchymal-like. These differences are mediated in part by the post-transcriptional regulation of BRM, which is expressed in SW13+ cells, and not detectable in SW13- cells. While treatment with histone deacetylase inhibitors (HDACi) can force cells to transition from SW13- to SW13+, the epigenetic mechanisms involved in the subtype switch are unknown. http://cancerres.aacrjournals.org/content/76/14_Supplement/1116
HDAC inhibitors: Valproic Acid (FDA approved drug), Butyrate (supplement available online), etc.
Recent publication (published in July 2016) demonstrating that Metformin kills ACC cells:
Metformin as a new anti-cancer drug in adrenocortical carcinoma http://www.ncbi.nlm.nih.gov/pubmed/27391065
“The anti-diabetic drug metformin has been associated with a decreased cancer prevalence and mortality in several solid tumors, prompting its possible use for ACC treatment. This paper evaluates the in vitro and in vivo anti-cancer effects of metformin using the ACC cell model H295R. Metformin treatment significantly reduces cell viability and proliferation in a dose- and time-dependent manner and associates with a significant inhibition of ERK1/2 and mTOR phosphorylation/activation, as well as with stimulation of AMPK activity. Metformin also triggers the apoptotic pathway, shown by the decreased expression of Bcl-2 and HSP27, HSP60 and HSP70, and enhanced membrane exposure of annexin V, resulting in activation of caspase-3 apoptotic effector. Metformin interferes with the proliferative autocrine loop of IGF2/IGF-1R, which supports adrenal cancer growth. Finally, in the ACC xenograft mouse model, obtained by subcutaneous injection of H295R cells, metformin intraperitoneal administration inhibits tumor growth, confirmed by the significant reduction of Ki67%.Our data suggest that metformin inhibits H295R cell growth both in vitro and in vivo. Further preclinical studies are necessary to validate the potential anti-cancer effect of metformin in patients affected by ACC.”
“The in vitro anti-proliferative effect of metformin in preclinical models is obtained by using higher doses than those reached in diabetic patients , thus apparently limiting its potential use in cancer treatment. However, in some tissues, metformin can accumulate at concentrations several-times higher than those found in the bloodstream , as demonstrated for the adrenal gland and liver . The adrenal gland is in fact one of the tissues expressing the highest levels of the organic cation transporters 1 (Oct 1) and 3 (Oct 3) , which are responsible for metformin cellular uptake and for its high concentration in this organ.”
“We demonstrated a significant decrease in both tumor growth rate and H295R cell proliferation within the tumor mass in metformin-treated ACC xenografted mice, associated with an increase in AMPK and a decrease in mTOR phosphorylation similar to that observed for in vitro-treated H295R. These results were obtained in vivo employing a metformin dosage very similar to that used in diabetic patients and in line with the literature on rodent tumor xenograft models [54, 55], supporting the hypothesis of metformin concentration in the ACC tumor”
“In conclusion, our findings provide the first preclinical report on the anti-proliferative and proapoptotic effect of metformin in ACC and help to elucidate the intracellular signaling pathways involved. Mitochondrial functions and integrity are also the key targets for the anti-cancer activity of this drug in adrenocortical cancer cells.”
Note: Metformin is an anti diabetic drug, very low cost and widely accessible. The typical dose used for its anti diabetic properties is 1g to 2g/day. Many private clinics in e.g. Germany are administrating Metformin to their cancer patients.
Gonadotropin releasing hormone antagonist treatment induces cell cycle arrest in gonadal somatic cell and adrenocortical tumours http://www.endocrine-abstracts.org/ea/0037/ea0037ep1134.htm
We have earlier shown that treatment with gonadotropin releasing hormone antagonist blocked adrenocortical tumour progression through gonadotropin suppression in inhibin Î±/SV40 T-antigen (inhÎ±/Tag) transgenic (TG) mice. Hereby, we investigated the molecular mechanisms underlying the GnRH antagonist (Cetrorelix acetate; GnRH-a) treatment induced potential antitumor effects on gonadal somatic cell and adrenocortical tumors in vivo and in vitro. In vitro treatment with 10 Î¼M GnRH-a significantly decreased cell viability and proliferation of murine KK1 (granulosa cell), BLT1 (Leydig cell), CÎ±1 (adrenocortical), all three lines originating from inhÎ±/Tag mice tumors, compared to respective non-treated controls. Flow cytometric analysis revealed a cell cycle arrest at G1 phase in all treated cell lines. We treated in vivo 6-mo-old inhÎ±/Tag mice bearing gonadal or 6.5-mo-old mice bearing adrenal tumors for 21 days, with either 3 mg/kg b.w./48 h i.p. of GnRH-a or vehicle. Treatments revealed a significant reduction of tumor burden in all types of tumours with GnRH-a treatment vs vehicle treated group. Our results suggest that GnRH-a treatment, besides blocking the release of gonadotropins, may also directly induce tumour cell death.
Unlike the GnRH agonists, which cause an initial stimulation of the hypothalamic-pituitary-gonadal axis (HPGA), leading to a surge in testosterone or estrogen levels, GnRH antagonists have an immediate onset of action, rapidly reducing sex hormone levels without an initial surge
Currently approved GnRH antagonists include the following: Cetrorelix, Ganirelix, Abarelix, Degarelix GnRH antagonists are administered by either intramuscular injection (abarelix) or subcutaneous injection (cetrorelix, degarelix and ganirelix).
Note: GnRH antagonists will trigger a histamine increase which in turn may lead to an increase of ACTH and finally Cortisole production. This means that you need to be ready to administrated anti histamines or Cortisole production inhibitors such as Ketoconazole.
It has been recently shown that a (relatively low cost) chemo therapy used for brain cancer may be effective in various forms of ACC:
Inhibition of Human Adrenocortical Cancer Cell Growth by Temozolomide in Vitro and the Role of the MGMT Gene http://press.endocrine.org/doi/pdf/10.1210/jc.2016-2768
I do believe this as I have seen RGCC chemosensitivity tests of ACC patient, where the test indicated that the ACC patient may respond to Temozolomide.
Thymoquinone from Nigella Sativa
Targeting polo-like kinase 1, a regulator of p53, in the treatment of adrenocortical carcinoma http://www.clintransmed.com/content/5/1/1
Thymoquinone is known to exert anti-inflammatory, anti-oxidative and antineoplastic activities  and strongly inhibits Plk1, but also other protein kinases such as Plk2, Plk3, Chk2, Pin1 and STAT3. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3533518/pdf/2162-3619-1-38.pdf
TQ may attain up to 27.8% of the volatile oil (w/w) composition. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3841989/?report=printable
Based on the above, Nigella Sativa oil should be helpful against ACCas it may contain up to 28% Thymoquinone.
Nigella Sativa oil can be found as supplement at online shops and can be taken orally or applied topically.
Response in a Patient With Metastatic Adrenal Cortical Carcinoma With Thalidomide http://jco.ascopubs.org/content/23/7/1579.full.pdf
She was started on thalidomide 100 mg per day, without side effects during the first month. The dose was then increased to 200mg per day. After 5months of treatment, she had gained 10 kg, and CT scan (Fig 2) showed partial response, which was a marked improvementfrom the CT scan of 6 months earlier (Fig 3). As of the publication date, she is asymptomaticand continues to take thalidomide200mg per day
Thalidomide is an angiogenesis inhibitor (Ref.) and indeed agiogenesis is known to stand out in ACC https://link.springer.com/article/10.1007/s12253-017-0259-6
Mebendazole monotherapy and long-term disease control in metastatic adrenocortical carcinoma. http://www.ncbi.nlm.nih.gov/pubmed/21454232
OBJECTIVE: To describe successful long-term tumor control in metastatic adrenocortical carcinoma, a relatively rare tumor with limited treatment options outside of surgery.
METHODS: We present the clinical, radiologic, and pathologic findings in a patient with failure of or intolerance to conventional treatments for metastatic adrenocortical carcinoma.
RESULTS: A 48-year-old man with adrenocortical carcinoma had disease progression with systemic therapies including mitotane, 5-fluorouracil, streptozotocin, bevacizumab, and external beam radiation therapy. Treatment with all chemotherapeutic drugs was ceased, and he was prescribed mebendazole, 100 mg twice daily, as a single agent. His metastases initially regressed and subsequently remained stable. While receiving mebendazole as a sole treatment for 19 months, his disease remained stable. He did not experience any clinically significant adverse effects, and his quality of life was satisfactory. His disease subsequently progressed after 24 months of mebendazole monotherapy.
CONCLUSION: Mebendazole may achieve long-term disease control of metastatic adrenocortical carcinoma. It is well tolerated and the associated adverse effects are minor.
Reversine is a Aurora kinase inhibitor http://theoncologist.alphamedpress.org/content/14/8/780.full
It has been used by a Dutch medical doctor (and cancer patient) to treat humans and from private sources I learned they saw very good success until they were shut down as they were not allowed to treat humans with not approved drugs. (the learning out of this is that Reversine can be accessible and was applied on humans with no specific toxicity)
Recently (end 2016), it has been shown that Aurora kinase inhibitors can be efficient in killing adrenal cancer metastases and some of the primary adrenocortical carcinoma but not all https://www.ncbi.nlm.nih.gov/pubmed/27177645
Inhibition of adrenocortical carcinoma by diphtheria toxin mutant CRM197 http://www.ncbi.nlm.nih.gov/pubmed/19996587
BACKGROUND: In this study, we investigated the effect of CRM197 treatment in human adrenocortical carcinoma (AC) implanted in nude mice. CRM197 is a non-toxic mutant of diphtheria toxin that binds heparin-binding epidermal growth factor-like growth factor (HB-EGF) which is implicated in the proliferative activity of several tumor cells.
METHODS: HB-EGF expression in AC cells was evaluated by reverse transcription PCR and Western blot. AC tumors were implanted in nude mice and then treated with CRM197. Effects of treatment on angiogenesis and apoptosis were investigated by immunohistochemistry and Western blot. The effects on cell invasion and migration were investigated with a matrigel invasion assay.
RESULTS: We demonstrated that human AC cells express HB-EGF. A treatment with CRM197 blocked growth, reduced angiogenesis and induced apoptosis in AC tumors implanted in nude mice. CRM197 also inhibited invasion and migration of these tumor cells.
CONCLUSIONS: These data support the evidence for anticancer properties of CRM197 in AC tumors.
Significance of heparanase-1 and vascular endothelial growth factor in adrenocortical carcinoma angiogenesis: potential for therapy. http://www.ncbi.nlm.nih.gov/pubmed/21706269
Anti-heparanase activity of ultra-low-molecular-weight heparin produced by physicochemical depolymerization. http://www.ncbi.nlm.nih.gov/pubmed/26453883
The antitumor drug etoposide (ETO) is widely used in treating several cancers, including adrenocortical tumor (ACT). However, when used at sublethal doses, tumor cells still survive and are more susceptible to the recurring tumor due to centrosome amplification. Here, we checked the effect of sublethal dose of ETO in ACT cells. Sublethal dose of ETO treatment did not induce cell death but arrested the ACT cells in G2/M phase. This resulted in centrosome amplification and aberrant mitotic spindle formation leading to genomic instability and cellular senescence. Under such conditions, Chk2, cyclin A/CDK2 and ERK1/2 were aberrantly activated. Pharmacological inactivation of Chk2, CDK2 or ERK1/2 or depletion of CDK2 or Chk2 inhibited the centrosome amplification in ETO-treated ACT cells. In addition, autophagy was activated by ETO and was required for ACT cell survival. Chloroquine, the autophagy inhibitor, reduced ACT cell growth and inhibited ETO-induced centrosome amplification. Chloroquine alleviated CDK2 and ERK, but not Chk2, activation and thus inhibited centrosome amplification in either ETO- or hydroxyurea-treated ACT cells. In addition, chloroquine also inhibited centrosome amplification in osteosarcoma U2OS cell lines when treated with ETO or hydroxyurea. In summary, we have demonstrated that chloroquine inhibited ACT cell growth and alleviated DNA damage-induced centrosome amplification by inhibiting CDK2 and ERK activity, thus preventing genomic instability and recurrence of ACT. http://www.nature.com/oncsis/journal/v4/n12/full/oncsis201537a.html
2016: Chloroquine enhances the efficacy of cisplatin by suppressing autophagy in human adrenocortical carcinoma treatment https://www.dovepress.com/chloroquine-enhances-the-efficacy-of-cisplatin-by-suppressing-autophag-peer-reviewed-article-DDDT
Statins and Mitotane
New publication showing that the combination of Mitotane with Statins may seriously improve the effectiveness of Mitotane treatment: “A significant positive association was found between the use of statin therapy and DCR at 6 months: 67% or 33% DCR was observed in patients treated or not with statins” http://press.endocrine.org/doi/pdf/10.1210/JC.2015-2080
AG (aminoglutethimide) and ETO (etomidate) inhibited cell proliferation in the NCI-h295 cells, but ETO was much more potent and showed antiproliferative effects at concentrations of 6 M. The growth inhibition was not reversed by administration of hydrocortisone. Our data demonstrate that adrenostatic compounds not only act by suppression of steroidogenic enzymes but can also influence both ACTH-R expression and cell proliferation in adrenal cells. As these effects occur in vitro at concentrations that are reached during treatment with theses drugs in patients, they are probably also of clinical relevance. Particularly the antiproliferative activity of ETO may be useful in Cushing’s syndrome due to adrenocortical cancer. The interaction of steroidogenesis, ACTH-R and glucocorticoid receptor expression as well as cell proliferation provides a new concept of the intra-adrenal response to stress in humans. http://www.klinikum.uni-muenchen.de/Medizinische-Klinik-und-Poliklinik-IV/Endokrinologisches-Forschungslabor/download/inhalt/pdf/Mechanisms_of_adrenostatic_compounds.pdf
Etomidate is given by intravenous push in a dose of 0.3 mg/kg http://www.uptodate.com/contents/sedation-or-induction-agents-for-rapid-sequence-intubation-in-adults
Here is the application procedure http://www.drugs.com/uk/etomidate-lipuro-2-mg-ml-emulsion-for-injection-leaflet.html
And here can be bought (with prescription) https://www.medizinfuchs.de/preisvergleich/etomidat-lipuro-10×10-ml-b.-braun-melsungen-ag-pzn-4442574.html
Cortisol levels have been reported to be suppressed up to 72 hours after a single bolus of etomidate https://en.wikipedia.org/wiki/Etomidate
The above suggests that ACTH up regulates ACTH-R which leads to an increase in Cortisol production which in turn further triggers the up regulation of ACTH-R leading to a continuous maintenance of this process. High local cortisol concentration causes further up-regulation of the ACTH-R and progrfession http://www.klinikum.uni-muenchen.de/Medizinische-Klinik-und-Poliklinik-IV/Endokrinologisches-Forschungslabor/download/inhalt/pdf/Mechanisms_of_adrenostatic_compounds.pdf
n-3 polyunsaturated fatty acids abrogate mTORC1/2 signaling and inhibit adrenocortical carcinoma growth in vitro and in vivo http://www.spandidos-publications.com/10.3892/or.2016.4720
Also reduces cachexia and cortisol.
The antiproliferative effects of ouabain and everolimus on adrenocortical tumor cells. http://www.ncbi.nlm.nih.gov/pubmed/24153038
Four clinically utilized drugs were identified and validated for treatment of adrenocortical cancer using quantitative high-throughput screening. http://www.ncbi.nlm.nih.gov/pubmed/22999104
Inhibition of Cortisole:
– In the present study, we found that digoxin inhibited adrenocorticotropin (ACTH)-stimulated release of corticosterone in rat adrenocortical cells both in vivo and in vitro. These results provide useful information on the regulation of anti-inflammation and glucose metabolism in response to digitalis. n the present study, we found that both basal and ACTH-stimulated production of corticosterone by ZFR cells is diminished by digoxin and digitoxin, but not by ouabain (Figure 2), a selective Na+,K+-ATPase inhibitor (Matsumoto et al., 2000). – These data indicate that digoxin and digitoxin decrease the corticosterone release by ZFR cells via a Na+,K+-ATPase-independent pathway.
– The inhibition of the conversion of corticosterone from deoxycorticosterone by digoxin and digitoxin (Figure 6) suggests that 11Î²-hydroxylase was inhibited by digitalis.
– These results indicate that digoxin and digitoxin inhibited the conversion of pregnenolone and progesterone to corticosterone and this implies that the activities of 3Î²-HSD and 11Î²-hydroxylase might be inhibited by digitalis. Digoxin and digitoxin were equally potent at inhibiting these enzymes.
– Since ouabain even at the same effective doses of digoxin and digitoxin failed to affect corticosterone production, we suggest that the inhibition of digitalis on corticosterone production might be independent of the action of Na+, K+-ATPase, although the present study did not prove that the production of corticosterone could not be inhibited by ouabain at higher doses
Inhibitory effect of bufalin and cinobufagin on steroidogenesis via the activation of ERK in human adrenocortical cells. http://www.ncbi.nlm.nih.gov/pubmed/21913902
Rosiglitazone impairs proliferation of human adrenocortical cancer: preclinical study in a xenograft mouse model. http://www.ncbi.nlm.nih.gov/pubmed/19955217
“PPARÎ³ is a nuclear transcription factor expressed in the adrenal cortex of normal tissue and in adrenal tumors [81,82]. Thiazolidinedione is a class of drugs that are ligands for PPARÎ³. Rosiglitazone is a thiazolidinedione that has been shown to have antiproliferative effects on several different cancers . In vitro and in vivo data demonstrate that thiazolidinediones have an antiproliferative effect on ACC cells [81,82,84–86]. Luconi et al. showed that treatment with rosiglitazone resulted in a significant reduction in tumor growth in the treated mice compared with the control group. In contrast to aggressive and more invasive tumors with abundant vascular network and high mitotic figures found in the control group, the tumors of the rosiglitazone-treated mice displayed a noninfiltrating margin, smaller vessels and apoptotic cells . Despite the promising results from preclinical work, the true mechanism responsible for decreased proliferation by rosiglitazone is not completely understood. Preclinical data suggest that rosiglitazone works through both PPARÎ³-dependent and PPARÎ³-independent pathways to cause growth arrest, cell death and decreased neovascularization [81,84,85]. Rosiglitazone inhibits ACC cell proliferation by interfering with Akt and ERK1/2 phosphorylation mediated by IGF-1 . PPARÎ³ antagonists may hold potential as a future treatment option for ACC.” (Ref.)
Small molecule modulators of Wnt/Î²-catenin signaling.http://www.ncbi.nlm.nih.gov/pubmed/23453073
Abnormal activation of the Wnt/Î²-catenin as well as the IGF2 signaling plays an important role in ACC development http://onlinelibrary.wiley.com/doi/10.1002/cphy.c140010/abstract?deniedAccessCustomisedMessage=&userIsAuthenticated=false
Update 16.02.2016 Funny enough, I identified Niclosamide as relevant to ACC long time ago and recently I found (indicated by a reader) this published paper: Identification of Niclosamide as a Novel Anticancer Agent for Adrenocortical Carcinoma http://clincancerres.aacrjournals.org/content/early/2016/02/12/1078-0432.CCR-15-2256.abstract
Triptolide induces apoptosis in human adrenal cancer NCI-H295 cells through a mitochondrial-dependent pathway http://www.ncbi.nlm.nih.gov/pubmed/21152873
Triptonide Effectively Inhibits Wnt/β-Catenin Signaling via C-terminal Transactivation Domain of β-catenin http://www.nature.com/articles/srep32779
Triptolide and triptonide are two key bioactive small molecules identified in a traditional Chinese medicine named Tripterygium wilfordii Hook F. (also known as the Thunder God Vine or lei gong teng). They are structurally similar and only differ in one chemical group at position 14, a carbonyl group in triptonide and a hydroxyl group in triptolide (Fig. 1A,B). Both triptolide and triptonide have been known to have a broad spectrum of biological functions such as immunosuppression, anti-inflammatory, anti-fertility and neuroprotective effects (Ref.).
Griseofulvin inhibits the growth of adrenocortical cancer cells in vitro http://www.ncbi.nlm.nih.gov/pubmed/23111828
Note: some hospitals in Germany seems to use this drug on their ACC patients going up to 1.5g/day with good result (source: private communications). Long term administrations seems to lead to no side effects but the liver functions have to be followed.
FDA approved drug. May be interesting since is an HB-EGF inhibitor and activates PPAR-Î´ receptors. Both mechanisms have been indicated as relevant for inhibition of ACC.
Potential of new anti-cancer agents targeting the nuclear translocation signaling of HB-EGF C-terminal fragments during the development of colitis-associated cancer http://www.scirp.org/journal/PaperInformation.aspx?PaperID=35615
TLR-4 activation and Immunomax (and Naltrexone in this context)
This is a very interesting angle on ACC (but also other cancers such as breast cancer):
TLR4 and CD14 have a reduced expression in ACC. Reintroduction of TLR4 expression in ACCs may provide a novel therapeutic strategy for adrenal cancer http://press.endocrine.org/doi/pdf/10.1210/jc.2010-1100
Immunomax, a Russian (low cost) vaccine containing polysaccharide purified from potato sprouts and suspended in a saline, is a TLR4 agonist already shown to have some anti cancer potential http://www.translational-medicine.com/content/12/1/322
Given the very low cost, very good safety profile and its potential for ACC as indicated above, Immunomax may be easily applied at home by any ACC patient.
Note: Naltrexone, often used in low dose (4.5mg/day) as an anti-cancer element, is an antagonist of TLR4 https://en.wikipedia.org/wiki/TLR4. Indeed, it seems that while ACC is characterised by a downregulation of TLR4, other cancers (such as lung cancer) may be overactive and may play important roles in promoting immune escape of cancer cells by inducing immunosuppressive cytokines and apoptosis resistance http://www.sciencedirect.com/science/article/pii/S0161589007000521. In such cases Naltrexone may be useful indeed. However, based on the research suggested above I would not suggest the use of Naltrexone (or LDN) in ACC.
More about impact of TLR4 modulation in cancer and TLR4 Immunomodulatory Agents http://journal.frontiersin.org/article/10.3389/fimmu.2014.00328/full
The vitamin A (retinol)-derived retinoic acids (RAs) are important regulators of a diverse spectrum of physiological processes, including cell proliferation, differentiation, morphogenesis, angiogenesis, and apoptosis.
Antitumoral effects of 9-cis retinoic acid in adrenocortical cancer https://www.researchgate.net/publication/242653013_Antitumoral_effects_of_9-cis_retinoic_acid_in_adrenocortical_cancer
9-cis retinoic acid, a novel treatment option for adrenocortical cancer? in vitro and in vivo studies http://www.endocrine-abstracts.org/ea/0032/ea0032oc4.6.htm
RGZ plus 9-cis retinoic acid further increased reporter activity http://www.ncbi.nlm.nih.gov/pubmed/15585569
Retinoic acid prevents experimental Cushing syndrome http://www.ncbi.nlm.nih.gov/pmc/articles/PMC209498/
Potential role for retinoic acid in patients with Cushing’s disease http://www.ncbi.nlm.nih.gov/pubmed/22851491 Experimental data have recently shown that retinoic acid restrains ACTH secretion
Adrenal retinoid receptors: new findings and new questions http://www.endocrine-abstracts.org/ea/0016/ea0016p46.htm
9-cis retinoic acid combined with Mitotane may lead to improved activity against ACC:
Evaluation of 9-cis retinoic acid and mitotane as antitumoral agents in an adrenocortical xenograft model http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4731638/
Other References: Ref1
Propranolol Therapy for Ectopic beta-Adrenergic Receptors in Adrenal Cushing’s Syndrome http://www.nejm.org/doi/full/10.1056/NEJM199711133372004
Tumour-derived human adrenocortical cells express beta-adrenergic receptors: steroidogenic effects of beta-adrenergic input. http://www.tandfonline.com/doi/full/10.1081/ERC-120016810
Presence of Ectopic β-Adrenergic Receptors on Human Adrenocortical Cortisol-Producing Adenomas – See more at: http://press.endocrine.org/doi/abs/10.1210/jcem-53-5-953#sthash.kX1WlKXo.dpuf
Vitamin D3 / 1α,25-Dihydroxyvitamin D2 / Calcitriol (not Calcitonin)
1α,25-Dihydroxyvitamin D2 inhibits the human H295R cell proliferation by cell cycle arrest: a model for a protective role of vitamin D receptor against adrenocortical cancer. http://www.ncbi.nlm.nih.gov/pubmed/24269839/
Slightly supra-physiological concentrations of 1α,25(OH)‚ D2 have a moderate anti-proliferative effect on H295R cells. Anti-proliferative effect was due to cell cycle arrest in G1 phase, without inducing apoptosis. The low mRNA expression levels at qRT-PCR as well as the weak immunohistochemical expression of VDR in ACC, suggests a protective role of VDR against malignant adrenocortical growth.
Another research pointing to the same positive role of Vitamin D2/D3:
Methylation Status of Vitamin D Receptor Gene Promoter in Benign and Malignant Adrenal Tumors https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4710947/
There is evidence that 1α,25(OH)2D3 protects against tumor formation by several VDR-mediated mechanisms, including regulation of growth arrest, cell differentiation, migration, invasion, and apoptosis, making it a candidate agent for cancer regulation … our findings represent the first evidence of an association between VDR gene promoter methylation and reduced VDR expression in ACC. This suggests a potential role of VDR epigenetic inactivation in malignant adrenocortical tumorigenesis. The VDR promoter methylation might be a target for pharmacological agents to treat adrenal cancer in selected cases.
Inhibition of Adrenal Cortical Steroid Formation by Procaine Is Mediated by Reduction of the cAMP-Induced 3-Hydroxy-3-methylglutaryl-coenzyme A Reductase Messenger Ribonucleic Acid Levels http://jpet.aspetjournals.org/content/307/3/1148.full
- In search of the mechanism mediating the action of procaine on cAMP-induced adrenal steroidogenesis, we first looked for an effect on the cAMP-induced PKA activity, mediating the effect of hormones on cholesterol transport into mitochondria and steroidogenic enzyme expression. PKA activity revealed that treatment with procaine did not affect this enzyme.
- Procaine did not affect the rate of steroid formation by cells incubated in the presence of 22R-hydroxycholesterol, a cholesterol derivative that can freely cross the mitochondrial membranes and directly load onto the P450scc enzyme as a substrate, suggesting that enzymes involved in the steroidogenic pathway were not affected by procaine treatment.
- Such an effect may be due either to a change in the rate of cholesterol transfer from intracellular stores into mitochondria or to an effect on cholesterol synthesis.
- Procaine had no effect on the expression levels of PBR and StAR, the two key regulatory proteins mediating the transfer of cholesterol into mitochondria
- Treatment of the cells with increasing concentrations of procaine resulted in the dose-dependent decrease of HMG-CoA reductase activity, assessed by the transformation of C-HMG-CoA into C-mevalonate. Maximal inhibition was achieved in the presence of 10 μM procaine.
- Considering the absence of a direct effect of procaine on HMG-CoA reductase activity measured in adrenal cell extracts, we hypothesized that procaine may act on HMG-CoA reductase mRNA levels.
- Procaine’s mechanism of action via the reduction of the cAMP-induced HMG-CoA mRNA levels offers an alternative approach to statins for regulating the HMG-CoA reductase activity.
- Procaine did not affect basal corticosteroid formation, suggesting that only pathological states of high glucocorticoid formation would be affected.
- We propose that such “corticosteroid synthesis modulators” may be valuable for the treatment of high-cortisol diseases such as AIDS, multiple sclerosis, AD, depression, and Cushing’s hypertension either alone or in combination with disease-specific therapies.
“ACAT1 functions in converting cellular cholesterol into cholesteryl ester in response to cholesterol abundance inside the cells. (In atherosclerotic lesions, where macrophages ingest excess cholesterol, the ability to esterify the newly-acquired cholesterol seems important for cell survival. Inhibition of ACAT1 may bring undesired consequences with destabilization of cellular membrane function upon cholesterol accumulation leading to macrophage cell death.)” Ref.
Cancer target of mitotane identified http://www.nature.com/nrendo/journal/vaop/ncurrent/full/nrendo.2015.156.html
A new study published in Endocrinology has identified sterol O-acyltransferase 1 (SOAT1) as the molecular target of mitotane in ACC cells:
“We demonstrate that mitotane is an inhibitor of Sterol-O-Acyl-Transferase 1 (SOAT1) leading to accumulation of these toxic lipids. In ACC tissue samples we show variable SOAT1 expression correlating with the response to mitotane treatment. In conclusion, mitotane confers adrenal specific cytotoxicity and down regulates steroidogenesis by inhibition of SOAT1 leading to lipid-induced ER-stress. Targeting of cancer specific lipid metabolism opens new avenues for treatment of ACC and potentially other types of cancer.” Ref.
Actually this is not that new. SOAT1 is the same as ACAT1. A team from University of Michigan has already converted this idea into a drug, ATR-101, which is currently in clinical trials against ACC. This drug is a ACAT1 inhibitor.
Natural ACAT inhibitors: piperine, esculeogenin A in tomatoes, Rubimaillin, Decursins, kuraridin, kushenol, leachanone, auraptene
The enhanced expression of ACAT-1 protein by leptin was suppressed by inhibitors of Janus-activated kinase2 (JAK2) and phosphatidylinositol 3-kinase (PI3K).
Inhibition of acyl-coenzyme A:cholesterol acyltransferase stimulates cholesterol efflux from macrophages and stimulates farnesoid X receptor in hepatocytes http://www.nature.com/emm/journal/v40/n4/full/emm200847a.html
Oleic acid anilide (OAA), a known ACAT inhibitor. Oleyl analide (OA) is a weak inhibitor of acylCoA:cholesterol acyltransferase (ACAT) with an IC50 of 26 µM. CAS# 5429-85-6
Bangaru ML, Woodliff J, Raff H, et al. Growth suppression of mouse pituitary corticotroph tumor AtT20 cells by curcumin: a model for treating Cushing’s disease. PLoS One. 2010;5(4):e9893.
Wnt/ß-catenin signaling inhibitors
Wnt/ß-catenin signaling inhibition it is believed to be a potential solution for treating ACC. Wnt/ß-catenin signaling inhibitors are: Niclosamide (anthelmintic drug available on eBay), Honokiol (magnolia natural extract available online as supplement – Honopure i the brand name), Salinomcyin (an antibiotic to which I allocated a specific section on this website)
Indomethacin and sulindac inhibition of ACTH stimulated cortisol release from adrenal glands in vitro. http://www.ncbi.nlm.nih.gov/pubmed/6306697
Phytoestrogen resveratrol suppresses steroidogenesis by rat adrenocortical cells by inhibiting cytochrome P450 c21-hydroxylase. http://www.ncbi.nlm.nih.gov/pubmed/16269870 Corticosterone production was inhibited 47% by 50 microM resveratrol in vitro and 20% ex vivo, while progesterone production was elevated to 400% of the control value in in vitro experiments. Resveratrol treatment decreased adrenal cytochrome P450 c21-hydroxylase expression in vivo and cell culture conditions.
Resveratrol reduces steroidogenesis in rat ovarian theca-interstitial cells: the role of inhibition of Akt/PKB signaling pathway. http://www.ncbi.nlm.nih.gov/pubmed/22719052 Resveratrol did not affect progesterone levels but reduced androgen production in a concentration-dependent fashion (androstenedione by up to 78% and androsterone by up to 76%).
Resveratrol potentiates effects of simvastatin on inhibition of rat ovarian theca-interstitial cells steroidogenesis. http://www.ncbi.nlm.nih.gov/pubmed/24524197 Resveratrol potentiated inhibitory effects of simvastatin on androstenedione and androsterone production in theca-interstitial cells. This suppressive effect correlated with profound inhibition in Cyp17a1 mRNA expression in the presence of a combination of resveratrol and simvastatin.
Fluconazole and acetazolamide in the treatment of ectopic Cushing’s syndrome with severe metabolic alkalosis http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4570129/
Cushing’s syndrome (CS) due to ectopic ACTH production accounts for about 10% of all types of CS and is frequently associated with metabolic alkalosis. Treatment of CS involves surgical resection and/or medical therapy to control hypercortisolism. We present the case of an 80-year-old woman affected by CS due to an unknown cause. The patient had severe metabolic alkalosis with refractory hypokalemia. To treat the underlying CS, fluconazole was initiated due to unavailability of ketoconazole. In spite of markedly decreasing cortisol levels, metabolic alkalosis persisted. Treatment of metabolic alkalosis with acetazolamide was thus initiated and pH levels successfully lowered. This case report shows that hypercortisolism can be effectively treated with fluconazole in cases where ketoconazole is unavailable or not tolerated and that persistent severe metabolic alkalosis caused by glucocorticoid excess can be safely and successfully treated with acetazolamide.
Note: in the study above the Fluconazole dose was increased step by step to about 1000mg/day and than lowered to about 400mg/day while its effectiveness remained high.
Verapamil and other Calcium Channel blockers
Calcium Channel blockers such as Verapamil can reduce cortisol production: ACTH1€“10 and ACTH11€“24 each elicit cortisol secretion submaximally in freshly dispersed or cultured beef adrenal cortical cells. The combination of ACTH1€“10 and ACTH11€“24 promotes cortisol release to the maximal level elicited by ACTH1€“24. Maximal cortisol release by ACTH11€“24, but not by ACTH1€“24 or ACTH1€“10, was enhanced by forskolin. The calcium channel blockers nifedipine and verapamil inhibited cortisol release by ACTH1€“10, ACTH1€“24 or ACTH11€“24, suggesting calcium influx to be essential for steroid secretion regardless of the secretogogue. Vanadium, in a dose-dependent manner, inhibited cortisol secretion elicited by ACTH1€“24 and ACTH1€“10 but not that caused by ACTH11€“24. These results suggest that there are at least two receptors mediating ACTH1€“24-dependent steroid secretion. One class of receptor recognizes ACTH1€“10 but not ACTH11€“24 and is linked to the cAMP messenger pathway. http://press.endocrine.org/doi/abs/10.1210/endo-125-2-592
When free extracellular concentration of Ca2+ was reduced to approximately 10 Î¼mol/l the cortisol response at all concentrations of TPA was reduced by approximately 25% indicating that protein kinase C activation is only partially dependent on extracellular calcium ions. This is confirmed by the effects of the voltage-dependant calcium channel blocker verapamil, which partially inhibited the cortisol response to a maximally effective concentration of TPA (1 Î¼mol/l). However, a second channel blocker, nitrendipine, proved to be ten times more potent than verapamil and totally inhibited the TPA response. http://joe.endocrinology-journals.org/content/117/3/423
Codeine and other Opioid agonists (i.e. avoid Naltrexone or LDN which is an antagonist?)
Effect of codeine and oxazepam on afternoon cortisol secretion in men: The objective of this study was to investigate the effects of oral codeine and oxazepam on afternoon cortisol secretion. Nine subjects received either oxazepam (30 mg) or codeine (30 mg) or placebo at 1700h on separate days in a counterbalanced design; the subjects were not aware of the sequence. Blood samples were collected with an indwelling intravenous catheter at 30-min intervals from 1500h to 1630h. Codeine, but not oxazepam, suppressed cortisol secretion. The trend of the declining cortisol values following codeine was significantly linear. These results are consistent with other evidence indicating the presence of an inhibitory opioid mechanism in the human hypothalamo-pituitary-adrenal (HPA) axis. The cortisol response to codeine may be a reliable and potentially useful paradigm for the study of the role of opioidergic mechanisms in HPA axis dysfunction. http://www.psyneuen-journal.com/article/0306-4530(89)90009-7/abstract http://www.ncbi.nlm.nih.gov/pubmed/2813660
Other References: Ref1,
In France, most preparations containing codeine do not require a doctor’s prescription. Example products containing codeine include Néocodion (codeine and camphor), Tussipax (ethylmorphine and codeine), Paderyl (codeine alone), Codoliprane (codeine with paracetamol), Prontalgine and Migralgine (codeine, paracetamol and caffeine) Available from online Franch pharmacy, e.g. https://www.moncoinsante.co.uk/paderyl-19-5-mg-phosphate-de-codeine-20-comprimes.html
In Denmark codeine is sold over the counter with max 9.6 mg in mixture. The item is given over the counter, no prescriptions. The strongest available over the counter preparation containing codeine has 9.6 mg (with aspirin, brand name Kodimagnyl); anything stronger requires a prescription.
In Canada tablets containing 8 mg of codeine combined with 15 mg of caffeine and 300 mg of paracetamol are sold as T1s (Tylenol Number 1) without a prescription.
Opioid agonists such as codeine sulfate have been shown to have a variety of effects on the secretion of hormones. Opioids inhibit the secretion of ACTH, cortisol, and luteinizing hormone (LH) in humans. They also stimulate prolactin, growth hormone (GH) secretion, and pancreatic secretion of insulin and glucagons in humans and other species, rats and dogs. Thyroid stimulating hormone (TSH) has been shown to be both inhibited and stimulated by opioids. http://www.rxlist.com/codeine-sulfate-drug/clinical-pharmacology.htm
Oxazepam and other Benzodiazepines
Benzodiazepine-induced sedation and cortisol suppression. A placebo-controlled comparison of oxazepam and nitrazepam in healthy male volunteers.: The sedative and cortisol suppressing properties of oxazepam (45 and 60 mg) and nitrazepam (10 and 15 mg) were examined in eight healthy male subjects. The most clear differences between oxazepam and nitrazepam were those seen with respect to the time course and until maximal effect (Tmax) of the different measurements. Nitrazepam showed maximal sedation after 1 h, maximal benzodiazepine level (RRA), and reaction time prolongation after 2 h, and maximal cortisol suppression after 3 h. Oxazepam showed maximal sedation after 2 h, maximal benzodiazepine levels, reaction time prolongation and cortisol suppression after 3 h. After administration of oxazepam (both doses) a transient return to baseline levels of cortisol was demonstrated. Whereas the degree of sedation correlated significantly within drug groups with the concurrent benzodiazepine levels, the Tmax of sedation was recorded 1 h earlier than the peak blood concentration (RRA) for both nitrazepam and oxazepam. The time course for cortisol suppression for the two compounds differed clearly from the other measurements and was not related to the peak blood concentration.
A supplement claimed to be effective in reducing cortisol levels:
Aminoglutethimide has two mechanisms of action:
It blocks aromatase in the generation of estrogens from androstenedione and testosterone.
It blocks the conversion of cholesterol to pregnenolone by inhibiting the enzyme P450scc and consequently decreases synthesis of all hormonally active steroids.
At low doses, aminogluthethimide is only an effective inhibitor of aromatase, but at higher doses, it effectively blocks P450scc as well.
Aminoglutethimide is abused by body builders and other steroid users to lower circulating levels of cortisol in the body and prevent muscle loss. Cortisol is catabolic to protein in muscle and effective blockade of P450scc by aminogluthethimide at high doses prevents muscle loss. https://en.wikipedia.org/wiki/Aminoglutethimide
Elements influencing Cortisol and Testosterone:
|Licorice (Glycyrrhizic acid)||Low||High||1,|
|Genistein (aromatse inhib)||Low||–||1,|
|Quercetin (aromatse inhib)||Low||–||1,|
Great overview on Cortisole lowering elements, from Life Extension:
Role of “old” pharmacological agents in the treatment of Cushing’s syndrome http://link.springer.com/article/10.1007/s40618-016-0462-4
And another great and recent (2016) overview on ketoconazole, metyrapone, etomidate, and mitotane http://link.springer.com/article/10.1007/s11102-016-0742-1
Pasireotide: a review of its use in Cushing’s disease. http://www.ncbi.nlm.nih.gov/pubmed/23605695
Chronic Melatonin Treatment Counteracts Glucocorticoid-Induced Dysregulation of the Hypothalamic-Pituitary-Adrenal Axis in the Rat https://www.researchgate.net/publication/13655007_Chronic_Melatonin_Treatment_Counteracts_Glucocorticoid-Induced_Dysregulation_of_the_Hypothalamic-Pituitary-Adrenal_Axis_in_the_Rat
Angiotensin II up-regulates monocarboxylate transporters expression in the rat adrenal gland. http://www.ncbi.nlm.nih.gov/pubmed/26828982: Angiotensin II (Ang II) is a major regulator of aldosterone secretion in the adrenal zona glomerulosa because it up-regulates the expression of a large number of genes involved in aldosterone biosynthesis. The transport of acetate across adrenocortical cells is a crucial step in the de novo synthesis of cholesterol, the steroid precursor of aldosterone. However, whether Ang II can affect this transport remains unknown. The current study aims to investigate the effect of in vivo infusion of Ang II on monocarboxylate transporters (MCT1, MCT2, and MCT4) gene expression in the rat adrenal gland. Immunohistochemical analysis and real-time PCR were used to examine the expression of MCTs at the protein and mRNA levels, respectively. The immunohistochemical analysis showed that higher numbers of cells expressed MCT1, MCT2, and MCT4 proteins in the zona glomerulosa and zona fasiculata of the adrenal cortex of Ang II-infused rats. Furthermore, real-time PCR indicated that in vivo infusion of Ang II increased the mRNA levels of MCT1, MCT2, and MCT4 in the rat adrenal gland. MCT up-regulation might maximize the intracellular transport of acetate in response to the stimulatory effect of Ang II on aldosterone secretion by the adrenal zona glomerulosa.
The above indicated that Angiotension II may lead to incraese in production of other hormones such as cortisol, due to the upreggulation of MCTs and thus penetration of acetate. On this line Angiotensin II inhibition should also reduce cortisol. Indeed, there are publications indicating that: Angiotensin II-stimulated cortisol secretion is mediated by phospholipase D. http://www.ncbi.nlm.nih.gov/pubmed/15249121 To inhibit Angiotensin II we may use angiotensin II receptor blockers (ARB) or angiotensin-
Ang II also enhances expression of the members of the AP-1 complex. Adrenal cell induction of the AP-1 proteins is regulated, not only by Ang II, but also by ACTH, basic fibroblast growth factor (b-FGF), insulin-like growth factor (IGF-I), and transforming growth factor beta (TGF-β). AP-1 proteins increase the expression of 11-beta-hydroxylase (CYP11B1) in rat and human adrenocortical cells. CYP11B1 (the 11-beta-hydroxylase enzyme) helps produce hormones called cortisol and corticosterone. (Ref)
Based on the above, Ang II has two mechanisms through which it can lead to increase production of cortisol in adrenal cells: 1. up-regulates MCTs and thus the fuel for hormone production, i.e. cholesterol (from acetate); 2. up-regulates AP-1 and thus the enzyme responsible for producing cortisol. Therefore, Ang II inhibition may be desirable in patients with functional ACC.
Here, is a list of Angiotensin II antagonists available on the market, i.e. FDA approved drugs: https://en.wikipedia.org/wiki/Angiotensin_II_receptor_antagonist
Dendritic cells as potential adjuvant for immunotherapy in adrenocortical carcinoma http://www.uniklinik-duesseldorf.de/fileadmin/Datenpool/einrichtungen/klinik_fuer_endokrinologie_diabetologie_und_rheumatologie_id5/dateien/NNR-Ca.pdf
Adrenocortical Carcinoma Treated by CyberKnife. http://www.ncbi.nlm.nih.gov/pubmed/27477410
Rifampicin (anti TBC antibiotic with anti cancer actions) leads to increased cortisol metabolism (Ref.)
AZEDRA for pheochromocytoma or paraganglioma: Although this page is dedicated to ACC related treatments, it may be good to mention a drug called AZEDRA (iobenguane) currently developed to treat malignant and/or recurrent pheochromocytoma or paraganglioma, another form of adrenal tumor. The drug is developed by Progenics Pharmaceuticals is currently in clinical trial phase. According to this report, the phase IIb clinical study, “conducted through the FDA’s Special Protocol Assessment program, met its primary endpoint, by demonstrating that 25% of 68 evaluable patients experienced a 50% or greater reduction in all antihypertensive medications for at least 6 months. The Phase IIb trial also showed that 92.2% of heavily pretreated patients who received at least one Azedra dose achieved partial response or stable disease.”
This site is not designed to and does not provide medical advice, professional diagnosis, opinion, treatment or services to you or to any other individual. Through this site and linkages to other sites, I provide general information for educational purposes only. The information provided in this site, or through linkages to other sites, is not a substitute for medical or professional care, and you should not use the information in place of a visit, call consultation or the advice of your physician or other healthcare provider. I am not liable or responsible for any advice, course of treatment, diagnosis or any other information, services or product you obtain through this site. This is just my own personal opinion regarding what we have learned on this road.