chapter 50 DHEA, the most abundant hormone in the body: inhibits glucose-6-phosphate dehydrogenase, inhibits the generation of NADPH, activates the pyruvate dehydrogenase complex and increases oxidative phosphorylation, increases oxidative stress, polarizes the immune system to M1/Th1, inhibits the pathway PI3K/Akt and decreases proliferation and increases apoptosis in cancer

José de Felippe Junior

DHEA: substance synthesized in the body with multiple actions – Plasma DHEA-sulphate declines from a peak at age maintain health, prevent diseases and help to heal them. JFJ 20, in both men and women. In men, DHEA-s ranges Warning: your adrenal gland is prohibited from making DHEA from 11 to 2.5 microM and in women from 6 to 1 mi- if you live in Brazil. Nonconformist medical doctors croM, from 20 to 80 years respectively (Labrie-1997). The DHEA biological actions involve multiple re- ceptors. DHEA binds to steroid/nuclear receptors (e.g. DHEA in United States of America is considered as a pregnane X receptor/steroid and xenobiotic receptor or food supplement, in Europe as a hormone that requires PXR/SXR), receptors alpha, beta (ER-alpha medical prescription (Samaras-2013) and in Brazil, for and ER-beta), (AR), cellular membrane re- reasons unknown, it is prohibited the commercializa- ceptors and endothelial cells receptors (activating tion and prescription. G-receptor-coupled proteins – GPCR) (Webb-2006, in – DHEA – is produced in Teng-2015). cortical adrenal gland and activated by sulfation in the It was found in Japanese with over 100 years in- liver and target organs. DHEA is the steroid hormone crease in telomere length in leukocytes, increased adi- or steroid pre-hormone in the highest amount in the ponectin concentration along with normal levels of body: 72% of the total (Ebeling-1994, Traish-2011). If DHEA-sulphate in blood, suggesting the importance of DHEA exists in such a high concentration in blood is this pre-hormone (Aoki-2017). because its importance in our economy is the same car- Most of the hormones in our body under physio- at. We dose in blood the DHEA-sulphate. logical conditions stimulate cell proliferation of normal DHEA-sulphate is the circulating form, and non-sul- cells and neoplastic cells: IGF-I, insulin, aldosterone, phated DHEA is the bioactive form with the various thyroxine, prolactin, , , DHEA, functions in cells and organs provided with sulfatases. while melatonin and DHEA- in a supra-physiological Non-sulphated circulating DHEA has no diagnostic dose causes antiproliferative effect in cancer. value in the blood because its effect is in the intimacy of DHEA deserves special attention because in physi- the tissues. Leukocytes, macrophages, peripheral ological doses it increases and testosterone lymph nodes, and spleen have sulfatases necessary to synthesis, both involved in normal or neoplastic cell convert DHEA-sulphate into DHEA and activate the proliferation. However, in high doses and in the short immune system. term, as in the treatment of neoplasias, DHEA inhibits

367 368 Integrative Medical Oncology – Pathophysiology and treatment

glucose-6-phosphate dehydrogenase (G6PD) and ease progresses. Therefore, given the importance of this causes anticancer effect by several mechanisms in most hormone or pre-hormone we must be alert to start as human cancer strains. soon as possible its correct replacement. We found studies in which high or above-normal To examine the association between circulating lev- DHEA increases breast cancer risk in postmenopausal els of dehydroepiandrosterone and dehydroepiandros- women (Gomes-1988, Dorgan-1997, Stoll-1999). Well, terone sulfate and the development of gastric cancer, elevated DHEA in the general population happens by the authors measured the serum levels of these uncontrolled replacement or more rarely by adrenal tu- in 13 individuals who donated serum to the Washing- mor. In postmenopausal or not, including in man, ex- ton County Maryland serum bank in 1974 and who cess DHEA inhibits G6PD, which causes a decrease in subsequently developed gastric cancer and in 52 NADPH generation and an increase in free radicals of matched controls. Prediagnostic serum levels of dehy- oxygen in a continuous and uninterrupted manner and droepiandrosterone were 38% lower in cases as com- the consequent continuous and uninterrupted oxida- pared to controls (P = 0.09). The risk of developing tive stress, which causes the increased risk of cancer. It gastric cancer increased with decreasing levels of both is inconsequential and sinful to replace DHEA, like any steroids. Adjustment for confounding factors such as other hormone, without the proper controls. smoking or the interval between blood donation and In physiological doses DHEA increases estrogen time to diagnosis did not alter the findings. These re- generation because it activates the critical enzyme in sults suggest that there may be a role for this steroid in the synthesis process, 3 beta-hydroxysteroid dehydro- the prevention of gastric cancer (Gordon-1993). genase type 1 and when placed in MCF-7 cell cultures Epidemiological studies show that the risk of devel- ER-positive breast cancer causes what it knows to do, oping specific cancers is related to the serum or urinary increased cell proliferation. Thomas showed this in levels of DHEA and DHEA-sulfate. In addition, dehy- 2011. We know that 3 beta-hydroxysteroid dehydroge- droepiandrosterone prevents a variety of spontaneous nase type 1 is a critical enzyme in the conversion of and chemically induced tumors when administered to DHEA to estradiol in breast tumors and also in normal laboratory animals (in-Gordon-1993). cells. The author showed that DHEA in physiological Dehydroepiandrosterone was found to inhibit ex- concentration increases the proliferation of ER-posi- perimental cancer development in mouse and rat lung, tive MCF-7 cells and the inhibition of the critical en- colon and mammary gland. Since DHEA is a potent zyme by two substances, trilostan or epostane, inhibits inhibitor of mammalian G6PD, the hypothesis that the DHEA-induced proliferation (Thomas-2011). compound could inhibit cell proliferation through an The author has shown only something that has inhibition of the pentose phosphate pathway has been been described in the literature since DHEA discovery. formulated. The authors studied the effects of DHEA Recently, in 317 breast cancer patients, there was no on the proliferation in vitro of human lymphocytes in- association between the concentration of DHEA or duced by several mitogens (PHA, ConA and PWM), DHEA-sulphate with breast cancer risk, in situ or inva- measuring 3H-thymidine uptake. DHEA inhibited sive. The relative risk (RR) of DHEA-non-sulphated, up- 3H-thymidine uptake of mitogen-stimulated cells from per limit versus lower quartile was RR, 1.2; (95% CI), both G6PD+ and G6PD- (mediterranean type defi- 0.8-1.8, p = 0.53 and DHEA-sulphate: RR, 1.3; (95% CI), ciency) individuals in a dose-dependent and reversible 0.9-2.0; p = 0.07, that is, non-significant (Tworoger-2006). fashion. These data suggest that the inhibition of thy- DHEA-sulphate was measured in 70 patients with midine uptake induced by DHEA on human lympho- solid tumors (gastrointestinal tract tumors: 28; breast cytes does not depend on the inhibition of G6PD (En- cancer: 24; non-small cell lung cancer: 18), 28 without nas-1987). and 42 with distant metástases. The control group con- It is interesting to note that physical activity in- sisted of 100 age- and sex-matched healthy subjects. creases the serum concentration of DHEA-sulphate in No significant difference in mean serum levels of normal or cancerous people. Particularly in breast can- DHEAS was observed between controls and non-met- cer survivors, twelve weeks of aerobic training im- astatic patients: both presented the expected physio- proves psychosocial health, along with increasing se- logical fall of DHEA-sulphate with advancing age. In rum DHEA-sulphate and decreasing salivary cortisol contrast, metastatic patients, irrespectively of tumor (Di Blasio-2017). histotype, showed significantly lower mean levels of In the general population, low levels of DHEA-sul- DHEAS with respect to either controls or non-meta- phate and increased cortisol/DHEA-s ratio correlates static patients (Lissoni-1998). with the onset of cancer, cardiovascular disease, meta- This study suggests that patients with metastases bolic syndrome, all causes of disease and higher mor- develop with exaggerated DHEA decrease as the dis- tality (Phillips-2010). Integrative Medical Oncology – Pathophysiology and treatment 369

The chemical name of DHEA is [(3S, 8R, 9S, 10R, 6. Drastically increases adiponectin gene expression 13S, 14S) -10,13-dimethyl-17-oxo-1,2,3,4,7,8,9,11,12,14 in omentum adipocytes. Adiponectin activates , 15,16-dodecahydrocyclopenta [a] phenanthren-3- AMPK, which inhibits mTOR: antiproliferation, yl] hydrogen sulphate of the formula: C 19 H 28 O 5 S, apoptotic and inhibition of peritumoral autophagy. and molecular weight: 368.5 g/mol. In addition, adipose tissue volume decrease. Other names: DHEA sulphate, sulphate; 7. Inhibits the most effective and frequent prolifera- DEHYDROEPIANDROSTERONE SULFATE, Dehy- tive axis PI3K/Akt (Jiang-2005). droisoandrosterone sulphate and DHEAS. 8. DHEA effects are mediated by Akt inhibition and It donates 1 electron and is acceptor of 5 electrons: subsequent activation of GSK-3beta, which causes oxidant molecule. mitochondrial depolarization, increase reactive ox- ygen species, activate membrane-redox-sensitive + O K voltage channels, and decrease intracellular Ca++, all anticancer effects. 9. Low DHEA-sulphate in the blood possibly increas- es the risk of metastases in patients with cancer al- H ready installed (Lissoni-1998). 10. For Hans Nieper DHEA increases serum cholines- O H O H H terase and the higher the concentration of this sub- S O stance, the greater the cancer regression. O 11. TP53 is tumor suppressor gene. DHEA sulfate trans- forms into intracellular DHEA in cells with inactive DHEA-sulphate p53 and triggers its activation (Nyce, 2018). 12. Various a) DHEA metabolites have antiproliferative activi- DHEA – molecular targets in cancer ty in several human cancer lines, Hep G2, Caco- 2 and HT-29. 1. Anti-Mycobacterium tuberculosis Metabolites: DHEA-sulphate, 7-oxygen deriva- a) Mycobacterium tuberculosis is one of the most tives of DHEA, , frequent causes of cancer, including the lung and and ethiocholanolone. DHEA increases tuberculostatics effectiveness. In addition malignant gliomas and lymphoma DHEA increases the proliferation of anti- with other metabolites (Yoshida-2003). gen-specific T cells and the production of IL-12 b) DHEA at 100 microM inhibits proliferation in and IFN-gamma in response to Mycobacterium almost 50% of hepatoma, Hep G2 cells and 30% tuberculosis infection and at the same time de- of colon adenocarcinoma, Caco-2 cells. creases IL-10, which causes the deviation from c) DHEA inhibits tumor of the breast, colorectal M2/Th2 to M1/​Th1 and increased cellular im- and lung in the mouse, via inhibition of G6PD munity (Angerami-2013). and decrease of NADPH (Schwartz-2016). 2. Inhibits the important enzyme glucose-6-phos- 13. Immunity phate dehydrogenase that decreases NADPH gen- a) Increases the activity of the pyruvate dehydroge- eration, reducing agent. G6PD inhibition dramati- nase (PDHc) complex in T lymphocytes and in- cally decreases neoplastic cell proliferation, creases the number and function of these cells. increases apoptosis and suppresses the effects of This is another mechanism of action of DHEA various tumor growth factors (Fang-2016, Stan- in cancer (Schriock-1994). ton-2012). b) Stimulates the maturation and activity of den- 3. DHEA increases oxidative phosphorylation in the dritic cells – enhances IFN-gamma and IFN-al- liver and brain: stimulates mitochondrial complex pha and thus polarizes the immune system to III and IV and the enzymes glutamate dehydroge- M1/​​Th1 (Leplina-2009). nase and succinate reductase from the Krebs cycle c) Increases the activity of Natural-Killer cells (in (Patel-2007-2008). Leprosy-2009) 4. Low DHEA is a contributing factor to the onset of d) Decrease of DHEA-sulphate in blood induces cancer and metabolic syndrome (Howard-2007) Th2 (Reed-1995) and this increases the risk of cancer. 14. Malignant gliomas 5. Antimutagenic effect and thus has a role in cancer a) (17alpha-AED), 3β-androstene-17β-diol (17β- chemoprophylaxis (Yang-2002). AED), 3β-androstene-7alpha, -17β-triol (7al- 370 Integrative Medical Oncology – Pathophysiology and treatment

pha-AET) and 3β-Androstene-7beta, -17be- b) DHEA provokes antiproliferative effect on hu- ta-triol (7beta-AET), DHEA metabolites are man breast cancer MCF-7 cells independent of produced in the neuroectodermal tissue. In the estrogen or (Gayosso- T98G and U251MG cells of glioblastoma and 2006). U937 of lymphoma these metabolites cause de- c) 7-betahydro-epiandrosterone, metabolite of creased proliferation and non-apoptotic cell DHEA, exerts antiestrogenic effects in breast death. The most potent metabolite is 17al- cancer: antiproliferative effect (Sandra-2012). pha-AED (Graf-2007). d) DHEA decreases proliferation and migration b) Glucose-6-phosphate dehydrogenase (G6PD) and increases breast cancer cells death. This is hinders the anticancer (oxidative) effect of gam- associated with cell cycle arrest in G1 phase and ma linolenic acid (GLA) on gliomas. DHEA in- MCF-7 cells death. DHEA also suppresses the hibits G6PD and increases the efficacy of GLA in migration of all breast cancer strains, regardless gliomas (Ramos-2003). of the presence of estrogen receptors, in vitro (in c) Radiation therapy in the brain tumor can cause López-Marure-2011). adrenal insufficiency and decrease the serum e) DHEA increases pyruvate dehydrogenase concentration of DHEA-sulphate in 4 of 10 irra- (PDHc) complex activity. Another important diated persons (Oberfield-1997) and especially and little known mechanism of action of DHEA in children. in cancer. d) CYP17A1 expression is significantly increased f) DHEA normal decreases some side effects of in gliomas, A172, U87MG and U373MG, which synthetic aromatase inhibitors in breast cancer secrete more DHEA than normal astrocytes. The (Gallicchio-2011). g) DHEA inhibits the invasion and migration of more proliferative and invasive the glioma be- breast cancer cells, MCF-7, MDA-MB-231, ZR- comes, the more CYP17A1 and DHEA are 75-30 because it decreases cytokines/chemok- over-regulated in the temozolomide-resistant ines and thereby causes a decrease in tumor (TMZ) strains. CYP17A1 is required for inva- growth. It should be used in the early stages of siveness and resistance to TMZ. In addition, the treatment of breast cancer in humans DHEA in physiological concentration markedly (López-Marure-2016). attenuates the effects of TMZ (Chuang-2017). h) DHEA inhibits MCF-7 breast cancer cells inva- e) Remember that DHEA in physiological concen- sion and migration, because it decreases IL-1al- tration is neuroprotective by attenuating oxida- pha, IL-6, IL-8 and TNF-alpha and thereby caus- tive stress and preventing neurodegenerative es decreased tumor growth. It should be used in diseases (Bastianetto-199, Aly-2011). the early stages of the treatment of breast cancer 15. Esophageal cancer in humans (Lopez-Marure-2016). a) Higher concentrations of dehydroepiandroste- i) There is a low concentration of DHEA and tes- rone (DHEA) were associated with a 38% de- tosterone in the saliva of women with breast creased risk of esophageal adenocarcinoma (EA) cancer (Dimitrakakis-2010). and gastric cardia adenocarcinoma (GCA). EA/ j) Polyunsaturated fatty acid omega-3 and DHEA GCA (OR per unit increase in log2 DHEA = induce MCF-7 breast cancer cells autophagy, via 0.62, 95% CI = 0.47 to 0.82, Ptrend = .001). PPAR-gamma activation. Do not affect normal Higher estradiol concentrations were associated cells (Rovito-2013) K- Twelve weeks of aerobic with a 34% reduced risk of EA/GCA (OR = 0.66, training improves the psychosocial health of 95% CI = 0.45 to 0.98, Ptrend = .05), and the breast cancer survivors, along with increasing association with free estradiol was similar (Pet- DHEA-sulfate and decreasing salivary cortisol rick-2018). (Di Blasio-2017). 16. Lung cancer k) In murine prolactin increases and DHEA de- a) Normal androsterone increases survival of lung creases breast carcinogenicity caused by car- cancer patients who underwent surgery (Pan- cinogenic chemical agent, DMBA (Koha- kov-1977). DHEA is a precursor of androste- ma-1997). rone. 18. Triple negative breast cancer 17. Breast cancer a) DHEA increases epithelial markers and decreas- a) DHEA decreases the proliferation and migra- es mesenchymal proteins from triple negative tion of human breast cancer cells MCF-7, estro- breast cancer cells, MDA-MB-231 and reduces gen receptor positive (Lopez-Marure-2011). tumor growth in vivo in a mouse xenotrans- Integrative Medical Oncology – Pathophysiology and treatment 371

planted model. Inhibition of migration occurs Testosterone exerts pro-apoptotic effects on pros- with reversal of the mesenchymal phenotype tate cancer cells (Anagnostopoulou-2013). (Colin-2017). f) Cytochrome P450 17A1 (CYP17A1) converts b) DHEA dramatically increases adiponectin gene Pregnenolone to DHEA and increases the pro- expression. Adiponectin significantly attenuates gression of and causes resistance the proliferation of two typical breast cancer to chemotherapy (in-Chuang-2017). Carcinoki- strains, MDA-MB231 and T47D. It promotes netic effect. apoptosis and stops the progression of the cell g) DHEA low serum sulfate predicts poor response cycle in the G0/G1 phase. Prolonged increase of of hormone therapy in patients with prostate adiponectin blocks Akt phosphorylation (inhib- cancer and bone metastases (Miyoshi-2016, its the pathway) and activates the GSK-3beta en- Yano-2017). zyme, suppresses the accumulation of beta-cat- h) , Orterenol and Galeterone enin and its nuclear activities and consequently inhibit only 90% of the enzyme 17α-hydroxy- reduces the expression of cyclin D1. Lithium lase-17,20-lyase (P450c17) which generates prevents this effect by inhibiting GSK-3beta. In DHEA in the intratumoral prostatic intimacy vivo reduction of tumorigenesis occurs in the (Penning-2018). We keep DHEA below normal mouse. Adiponectin represents a new treatment levels in prostate cancer because it is carcinoki- for breast cancer and DHEA increases the ex- netic. It is not carcinogenic. pression of the adiponectin gene (Hernan- i) Post- androgen deprivation therapy initiation, dez-Morante-2006). authors measured samples in 219 patients as c) DHEA decreases the proliferation and migra- well as two subsequent annual samples in a sub-

tion of human breast cancer cells MDA-MB-231 set of 101 patients. Higher tertiles of estrone (E1)

and Hs578T, estrogen receptor negative and estradiol (E2) were significantly associated (López-Marure-2011). with sooner time to castration-resistant prostate d) DHEA inhibits the invasion and migration of cancer. In patients with longitudinal samples, in- breast cancer cells, MDA-MB-231, ZR-75-30, creases in serum DHEA and androsterone were because it decreases IL-1alpha, IL-6, IL-8 and significantly associated with sooner time to cas- TNF-alpha. It causes a decrease in tumor growth tration-resistant prostate câncer (Toren-2018). and the author advises the use in the early stages j) AR Signaling in Prostate Cancer Regulates a of the treatment of breast cancer in humans (Lo- Feed-Forward Mechanism of Androgen Synthe- pez-Marure-2016). sis by Way of HSD3B1 Upregulation (Hettel- 19. Prostate cancer 2018). a) DHEA blood low level correlates with increased k) Beyond T and DHT – novel steroid derivatives severity, higher Gleason score and advanced capable of wild type androgen receptor activa- clinical stages of prostate cancer. DHEA level is tion: 11-deoxcorticosterone (DOC) and 11be- useful as a prognostic factor in patients with this ta-hydroxyandrostenedione (11OH-AED) (Mo- problem (Miyoshi-2016). staghel-2014). b) In vitro DHEA increases prostatic cancer cells 20. Gastric cancer proliferation via androgen and estrogen. In clin- a) Higher concentrations of dehydroepiandroste- ical the effects of DHEA on prostate function are rone (DHEA) were associated with a 38% de- unknown. The paper has suspect conflict of in- creased risk of esophageal adenocarcinoma (EA) terest (Liu-2010). and gastric cardia adenocarcinoma (GCA). EA/ c) DHEA at low levels is associated with worsening GCA (OR per unit increase in log2 DHEA = prostate cancer. 0.62, 95% CI = 0.47 to 0.82, Ptrend = .001). d) Carcinokinetic effect of estrogenic activity Higher estradiol concentrations were associated ER-alpha > Cadmium chloride > Antimony with a 34% reduced risk of EA/GCA (OR = 0.66, chloride > Lithium hydroxide > Barium chloride 95% CI = 0.45 to 0.98, Ptrend = .05), and the > Sodium selenite > Chromium chloride (Choe- association with free estradiol was similar (Pet- 2003). rick-2018). e) DHEA activates the NGF receptor (nerve growth 21. Colon cancer factor) phosphorylates TrkA (tropomyosin-relat- a) DHEA inhibits growth and causes G2/M cell cy- ed kinase) and p75 (neurotrophin receptor) and cle arrest in human colon adenocarcinoma HT- decreases apoptosis of prostate cancer cells. This 29 SF cells via inhibition of the isoprenylation of anti-apoptotic effect is reversed by testosterone. some proteins (Schulz-1992). 372 Integrative Medical Oncology – Pathophysiology and treatment

b) In human colon cancer HT-29 cells proliferation in humans, DHEA inhibits the proliferation of is dose-dependent and time-dependent inhibi- hepatocellular carcinoma with 100 to 200mi- tion with accumulation of cells in the G0/G1 croM (in- Ho-2008). phase. By inhibiting the PI3K/Akt pathway, it j) FASTKD2 (FAST kinase domain-containing causes apoptosis. Effect is lower than that ob- protein 2) is an important regulator of mito- served in HepG2 cells (Jiang2005). chondrial physiology. DHEA significantly re- c) DHEA inhibits PRL-3 (phosphatase of regener- duces the expression of FASTKD2 and causes ating liver-3) prenylation and may prevent or significant reduction of proliferation, colony delay the onset of metastatic colon cancer (Sun- formation and growth in semi-solid medium in dar-2013). SK-Hep-1 cells of the hepatoma. Mitochondrial d) DHEA at 100 microM inhibits proliferation in depolarization, increased mitochondrial mass 30% of Caco-2 cells from colon adenocarci­ and decreased respiratory activity occur. Reac- noma. tive oxygen species increase in tumor cells 22. Hepatoma (Cheng-2016). a) The incidence of hepatoma is 2 to 4 times higher 23. Pancreatic cancer in men than in women, possibly due to the pro- a) DHEA inhibits the proliferation of pancreatic tective role of estrogen and androgen stimulant carcinoma cells, MiaPaCa-2, Capan-1, Capan-2, (El-Serag-2011, Dorak-2012, Yang-2012). CAV and Panc-1 in vitro and in vivo. Tumor vol- b) DHEA triggers autophagic death in hepatoma ume decreases from 53 to 73% (Melvin-1997). cells, HepG2 via JNK mediated by increased ex- b) DHEA via oral ad libitum in water (0.6%) inhib- pression of p62/SDSTM1 (Vegliante-2016). its the growth of pancreatic cancer in the athy- c) Inhibits the activity and gene expression of 3-hy- mic mouse. There is a significant increase in the droxy-3-methylglutaryl CoA reductase in rat: serum concentration of DHEA-sulfate, testos- antiproliferative pre-neoplastic liver nodules terone and progesterone. In the treated group, (Pascale-1995). DHEA-s is 50-fold higher than in the control d) Inhibits nuclear transcription factor NF-kappaB group. There was no weight reduction or side ef- in hepatocytes (Yasumasa-2004). fects (Muscarella-1998). e) DHEA. Antiproliferative effect on hepatoma by c) DHEA injected intraperitoneal sulfate inhibits mechanism of action other than inhibition of the growth of xenotransplanted pancreatic can- glucose-6-dehydrogenase-G6PD decreasing the cer in the mouse (in-Muscarella-1998). expression and function of mitochondrial genes d) Five days of DHEA (G6PD inhibitor) in MIA and depleting mitochondrial ATP generation. cell culture of pancreatic cancer inhibits prolif- Controversial. Possible methodological error eration by 23%. When in combination with oxy- (Ho-2008). thyamine (inhibition of transketolase) the inhi- f) In HepG2 cells of human hepatoma, the prolif- bition reaches 60% (Boros-1997). eration is drastically dose-dependent and 24. Endometrial cancer time-dependent with accumulation of cells in a) When DHEA inhibits G6PD in HeLa cervical the G0/G1 phase. By inhibiting the PI3K/Akt carcinoma cells, there is a proliferation and mi- pathway, it causes apoptosis (Jiang2005). gration decrease because of the disorganization g) DHEA at 100 microM inhibits proliferation in of the microfilaments and microtubules of the almost 50% of the hepatoma Hep G2 cells. cytoskeleton caused by the increase of oxygen h) MicroRNA-21 (miR-21) is elevated one to ten free radicals (increase in the redox potential). fold in human hepatocarcinoma and down-reg- The author concludes, “suppression of G6PD ulates the expression of various tumor suppres- may be a promising strategy in the development sor genes, including PCD4 (Programmed Cell of new therapeutic methods for cervical cancer” Death 4). Ten low-dose DHEA nanoM activates (Fang-2016). the G-protein coupled to the estrogen receptor 25. Melanoma and rapidly stimulates the transcription of miR- a) Normal DHEA decreases the risk of melanoma 21 in human hepatocellular carcinoma. At the and squamous cell carcinoma (Alberg-2001). end neoplastic proliferation increases (Teng- b) DHEA inhibits growth by inducing differentia- 2015). High doses inhibit proliferation in several tion in murine melanoma B16 cells (Kawai-1995). studies. 26. Multiple myeloma i) In rats, DHEA induces dose-, gender- and ce- a) Dehydroepiandrosterone can inhibit the prolif- pa-dependent hepatocellular tumor. In contrast, eration of myeloma cells and the interleukin-6 Integrative Medical Oncology – Pathophysiology and treatment 373

production of bone marrow mononuclear cells 2. Alberg AJ, Gordon GB, Genkinger JM, et al. Serum dehydroepian- from patients with myeloma (Liu-2005). drosterone and dehydroepiandrosterone sulfate and risk of mela- 27. Renal carcinoma noma or squamous cell carcinoma of the skin. Anticancer Res. 21(6A):4051-4;2001. a) Increased serum cortisol levels are associated 3. Aly HF, Metwally FM, Ahmed HH. Neuroprotective effects of dehy- with high tumour grade in patients with renal droepiandrosterone (DHEA) in rat model of Alzheimer’s disease. cell carcinoma (Rasmuson-2001). Acta Biochim Pol. 58(4):513-20;2011. 28. Others 4. Anagnostopoulou V, Pediaditakis I, Alkahtani S, et al. Differential a) Post-menopausal DHEA increases bone mineral effects of dehydroepiandrosterone and testosterone in prostate and density, decreases insulin resistance and fat colon cancer cell apoptosis: the role of nerve growth factor (NGF) mass, and exerts estrogenic effect on vaginal cy- receptors. Endocrinology. 154(7):2446-56;2013. 5. Angerami M1, Suarez G, Pascutti MF, et al. Modulation of the phe- tology without stimulating the endometrium notype and function of Mycobacterium tuberculosis-stimulated (Perzylo-2011). dendritic cells by adrenal steroids. Int Immunol. 25(7):405-11;2013. b) DHEA in post-menopausal long-term and low- 6. Aoki Y, Aoki M, Yamada K. Leukocyte Telomere Length and Serum dose in the early or late phase of menopause Levels of High-Molecular-Weight Adiponectin and Dehydroepian- modulates endocrine parameters and the syn- drosterone-Sulfate Could Reflect Distinct Aspects of Longevity in thesis of neuroactive steroids. Supplementation Japanese Centenarians. Gerontol Geriatr Med. 3:233372141769 is beneficial (Genazzani-2003). 6672;2017. 7. Bastianetto S, Ramassamy C, Poirier J, Quirion R. Dehydroepian- c) Low DHEA in elderly woman and low testoster- drosterone (DHEA) protects hippocampal cells from oxidative one in elderly man increases risk of dying (Fu- stress-induced damage. Brain Res Mol Brain Res. 66(1-2):35-41; kai-2011). 1999. d) The higher the ratio between serum cortisol and 8. Boros LG, Puigjaner J, Cascante M, et al. Oxythiamine and dehy- DHEA, the higher the incidence of metabolic droepiandrosterone inhibit the nonoxidative synthesis of ribose syndrome in the population. Cortisol gives us an and tumor cell proliferation. Cancer Res. 57(19):4242-8;1997. idea of ​​the degree of stress and it is known that 9. Cheng ML, Chi LM, Ho HY. Dehydroepiandrosterone-induced changes in mitochondrial proteins contribute to phenotypic altera- the greater the stress the greater the peripheral tions in hepatoma cells. Biochem Pharmacol. 117:20-34;2016. resistance to insulin. Low DHEA correlates with 10. Choe SY, Kim SJ, Kim HG, et al. Evaluation of estrogenicity of major peripheral insulin resistance. Thus, the results of heavy metals. Sci Total Environ. 312(1-3):15-21;2003. the present study show once again the impor- 11. Colín-Val Z, González-Puertos VY, Mendoza-Milla C, et al. DHEA tance of stress and low levels of DHEA in daily increases epithelial markers and decreases mesenchymal proteins in life (Phillips-2010). breast cancer cells and reduces xenograft growth. Toxicol Appl e) In polycystic ovarian syndrome, atorvastatin de- Pharmacol. 333:26-34;2017. 12. Chuang JY, Lo WL, Ko CY, et al. Upregulation of CYP17A1 by Sp1- creases the concentration of DHEA-sulphate mediated DNA demethylation confers temozolomide resistance and (Sathypalan-2012). through DHEA-mediated protection in glioma. Oncogenesis. 6(5): e339;2017. 13. Di Blasio A, Morano T, Cianchetti E, et al. Psychophysical health Conclusion status of breast cancer survivors and effects of 12 weeks of aerobic training. Complement Ther Clin Pract. 27:19-26;2017. DHEA is an important body hormone and we must re- 14. Dimitrakakis C, Zava D, Marinopoulos S, et al. Low salivary testos- spect the normal physiology knowing perfectly the terone levels in patients with breast cancer . BMC Cancer. 10:547, right time to make the replacement either in health or 2010. in illness. 15. Dorak MT, Karpuzoglu E. Gender differences in cancer susceptibil- ity: an inadequately addressed issue. Front Genet. 3:268;2012. We urgently need to send to the National Health 16. Dorgan JF, Stanczyk FZ, Longcope C, et al. Relationship of serum Surveillance the numerous papers on DHEA benefits dehydroepiandrosterone (DHEA), DHEA sulfate, and 5-andros- in maintaining health, preventing and treating diseas- tene-3 beta, 17 beta-diol to risk of breast cancer in postmenopausal es. One voice only is like the fable of the “swallow”. women. Cancer Epidemiol Biomarkers Prev. 6(3):177-81;1977. Now the question remains. 17. 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