scholarly journals Determination of Enzyme Inhibition Potential and Anticancer Effects of Pistacia khinjuk Stocks Raised in In Vitro and In Vivo Conditions

Agronomy ◽  
2021 ◽  
Vol 11 (1) ◽  
pp. 154
Author(s):  
Emine Ayaz Tilkat ◽  
Hayri Batibay ◽  
Ismail Yener ◽  
Pelin Koseoglu Yilmaz ◽  
Mehmet Akdeniz ◽  
...  
Keyword(s):  
Enzyme Inhibition ◽  
Shoot Cultures ◽  
Root Extracts ◽  
Bche Activity ◽  
Pistacia Khinjuk ◽  
Cell Series ◽  
Ht 29 ◽  
Mcf 7

In this study, antihypertensive, anticholinesterase, antiurease, antityrosinase and antielastase enzyme inhibition and anticancer activities of in vivo (male and female) and in vitro samples (root, stem and leaf parts) of the Pistacia khinjuk Stocks were investigated comparatively. In this context, in vitro shoot cultures were obtained from germinated mature seeds. Then, the juvenile shoots were proliferated in Murashige and Skoog (MS) medium supplemented with 1 mg/L 6-Benzylaminopurine (BAP). In terms of anticancer activity, the whole of the samples studied was found to have apoptotic effects against MCF-7 (breast cancer) and HT-29 (colon cancer) cell lines. The extracts obtained from in vivo female root parts showed better cytotoxicity than all the other tested extracts on MCF-7 (IC50: 31.86 ± 1.40 µg/mL) and HT-29 cell series (IC50: 59.60 ± 0.69 µg/mL). Even though all the samples showed a strong butyrylcholinesterase enzyme inhibition (BChE) activity, it was detected that none of the samples had shown acetylcholinesterase enzyme inhibition (AChE). It was also determined that in vivo leaf samples of female trees had the highest BChE activity (Inhibition%: 75.20 ± 1.50). All the samples showed a low-moderate level of urease and tyrosinase enzyme activity, while in vivo samples showed a significant level of the elastase enzyme activities (Inhibition%: 58.72 for female root extracts; 58.25 for female leaf extracts, at 50 µg/mL concentration), and they were more active than the standard oleanolic acid (Inhibition%: 39.46 ± 0.52). The antihypertensive activities as the inhibition of angiotensin I-converting enzyme (ACE) of in vivo samples (Inhibition%: 95.88 for female stem extracts; 95.18 for female root extracts) were detected as close to the standard (Inhibition%: 96.64 ± 1.85) used. In general, it can be stated that in vivo samples had higher biological activities compared to in vitro ones. Consequently, according to our results, it was concluded that in vitro stem parts of khinjuk pistachio could also be evaluated as an alternative new antihypertensive, antielastase and anticancer agent source.

Derivatives of Deoxypodophyllotoxin Induce Apoptosis Through Bcl-2/Bax Proteins Expression

2020 ◽  
Vol 20 ◽  
Author(s):  
Ya-Nan Li ◽  
Ni Ning ◽  
Lei Song ◽  
Yun Geng ◽  
Jun-Ting Fan ◽  
...  
Keyword(s):  
Annexin V ◽  
Mtt Method ◽  
Anthriscus Sylvestris ◽  
Anti Tumor Activity ◽  
Derivatives Of ◽  
Toxicity In Vitro ◽  
Ht 29 ◽  
Mcf 7

Background: Deoxypodophyllotoxin, isolated from theTraditional Chinese Medicine Anthriscus sylvestris, is well-known because of its significant antitumor activity with strong toxicity in vitro and in vivo. Objective: In this article, we synthesized a series of deoxypodophyllotoxin derivatives, and evaluated their antitumor effectiveness.Methods:The anti tumor activity of deoxypodophyllotoxin derivatives was investigated by the MTT method. Apoptosis percentage was measured by flow cytometer analysis using Annexin-V-FITC. Results: The derivatives revealed obvious cytotoxicity in the MTT assay by decreasing the number of late cancer cells. The decrease of Bcl-2/Bax could be observed in MCF-7, HepG2, HT-29 andMG-63 using Annexin V-FITC. The ratio of Bcl-2/Bax in the administration group was decreased, which was determined by the ELISA kit. Conclusion: The derivatives of deoxypodophyllotoxin could induce apoptosis in tumor cell lines by influencing Bcl-2/Bax.

scholarly journals Biological significance of naturally occurring deuterium: the antitumor effect of deuterium depletion

2010 ◽  
Vol 151 (36) ◽  
pp. 1455-1460 ◽  
Author(s):  
Gábor Somlyai ◽  
Miklós Molnár ◽  
Gábor Laskay ◽  
Mariann Szabó ◽  
Tamás Berkényi ◽  
...  
Keyword(s):  
Antitumor Effect ◽  
Biological Significance ◽  
Human Melanoma ◽  
Naturally Occurring ◽  
Ht 29 ◽  
Mcf 7

A felszíni vizekben a deutérium (D) koncentrációja több mint 16 mmol/l (150 ppm), az élő szervezetekben 10 mmol/l fölötti. A csökkentett deutériumtartalmú (30±5 ppm) vízzel folyó kutatások során korábban azt tapasztalták, hogy a deutériummegvonás gátolta a sejtosztódást in vitro különböző tumoros sejtvonalakban (PC-3, humán prosztatatumor; MDA, humán emlőtumor; HT-29, humán vastagbéltumor; M14, humán melanoma). A csökkentett deutériumtartalmú víz tumorregressziót idézett elő humán eredetű tumorral xenotranszplantált, immunszuppresszált egerekben (MDA és MCF-7 humán emlőtumor, PC-3 prosztatatumor), és apoptózist indukált in vitro és in vivo . A csökkentett deutériumtartalmú víz (25±5 ppm) részleges vagy teljes tumorregressziót idézett elő spontán tumoros kutyákban és macskákban. A készítményt 1999-ben daganatellenes állatgyógyszerként törzskönyvezték (Vetera-DDW-25 A.U.V., 13/99 FVM). Injekciós változatát klinikai vizsgálatban sikeresen tesztelték. Az Országos Gyógyszerészeti Intézet 5621/40/95 számú engedélye alapján, a GCP-elvek betartásával lefolytatott randomizált, kettős vak elrendezésű humán fázis II klinikai vizsgálat szignifikáns különbséget igazolt a kontroll- és a kezelt csoport között a vizsgált paraméterek vonatkozásában. Egyéves utánkövetés során a csökkentett deutériumtartalmú víz szignifikánsan csökkentette a prosztatatumoros betegek halálozási arányát, miközben a túlélés hosszát szignifikánsan növelte. Az eredmények azt igazolják, hogy a sejtek képesek szabályozni a deutérium/hidrogén (D/H) arányát és ennek változtatásával elindítani bizonyos molekuláris folyamatokat, amelyeknek kulcsszerepük van a sejtciklus szabályozásában. Feltételezzük, hogy nem az intracelluláris pH változása, hanem az azt kísérő D/H arány változása adja meg a sejteknek a jelet az S-fázisba lépéshez. A D-koncentráció csökkenése beavatkozik a szignáltranszdukciós folyamatokba, így idézve elő a tumor regresszióját. A D szerepének felismerése a sejtosztódás szabályozásában új lehetőségeket nyit meg a daganatterápia és a megelőzés területén, hozzájárulva ezzel a jelenlegi daganatellenes terápiák hatékonyságának növeléséhez.

scholarly journals Χαρακτηρισμός βιολογικών δράσεων ενεργών συστατικών αιθέριων ελαίων

2017 ◽  
Author(s):  
Ελένη Φίτσιου
Keyword(s):  
Pistacia Lentiscus ◽  
Lippia Citriodora ◽  
Ht 29 ◽  
Satureja Thymbra ◽  
Mcf 7

Τα αρωματικά φυτά είναι γνωστά για τις ποικίλες ιδιότητές τους από την αρχαιότητα ένα μεγάλο μέρος των οποίων οφείλεται στα αιθέρια έλαια που αποτελούν δευτερογενείς μεταβολίτες. Σήμερα, τα αιθέρια ελαία μελετώνται για τις βιολογικές τους ιδιότητες, ανάμεσα στις οποίες συγκαταλέγεται η χημειοπροληπτική τους δράση, δηλαδή ένας συνδυασμός ενδοκυτταρικών μηχανισμών δράσης συμπεριλαμβανομένων της αντιοξειδωτικής, αντιφλεγμονώδους και προ-αποπτωτικής. Στόχος της έρευνάς μας ήταν να ελέγξουμε έναν αριθμό φυσικών εκχυλισμάτων από ελληνικά φυτά για την πιθανή χημειοπροληπτική τους δράση και να μελετήσουμε περαιτέρω τα πιο υποσχόμενα για τους μοριακούς μηχανισμούς δράσης τους. Πενήντα φυτικά εκχυλίσματα ελέγχθηκαν για την ικανότητα τους να απενεργοποιούν ελεύθερες ρίζες in vitro (τεχνικές DPPH και ABTS). Παράλληλα, 10 αιθέρια έλαια ελέγχθηκαν για την αντιπολλαπλασιαστική τους δράση εναντίον διαφορετικών καρκινικών κυτταρικών σειρών in vitro (Caco2, HepG2, MCF-7) (τεχνική SRB) και αναλύθηκε η χημική τους σύσταση. Τα περισσότερα αιθέρια έλαια είχαν ως κύρια συστατικά τερπένια και τερπενοειδή, ενώ συνολικά την σημαντικότερη δράση επέδειξαν τα έλαια των φυτών Satureja thymbra, Origanum dittany Lippia citriodora (λουίζα) και Pistacia lentiscus var. Chia (μαστίχα). Μετά το τέλος της σάρωσης επιλέξαμε τα δύο τελευταία, καθώς και τα κυριότερα συστατικά τους για περαιτέρω μελέτες. Τα δύο κυριότερα συστατικά του μαστιχέλαιου, α-πινένιο και μυρκένιο, δεν παρουσίασαν σημαντική αντιοξειδωτική δράση, ενώ το έλαιο της λουίζας, παρουσίασε ισχυρότερη δράση από το κύριο συστατικό του, citral. Με εξαίρεση το μυρκένιο, όλοι οι παράγοντες εμφάνισαν υψηλή αντιπολλαπλασιαστική ικανότητα in vitro, η οποία συνδέεται με την ικανότητά τους να προκαλούν βλάβες στο DNA, ενώ τα δύο έλαια επέδειξαν και σημαντική ογκοκατασταλτική δράση in vivo. Χρησιμοποιώντας κυτταρομετρία ροής παρατηρήθηκε αναστολή του κυτταρικού κύκλου στη φάση G2/M σε διαφορετικές κυτταρικές σειρές, με παράλληλη αλλαγή στην έκφραση γονιδίων που σχετίζονται με τον κυτταρικό κύκλο (cyclinA, B1, D, E, p53, p21, survivin) για τη λουίζα και το citral. Επίσης, παρατηρήσαμε πως κανένα φυτοχημικό δεν επάγει την κλασσική απόκριση της απόπτωσης σε καρκινικά κύτταρα παχέος εντέρου (για τις δεδομένες χρονικές επωάσεις και συγκεντρώσεις που χρησιμοποιήθηκαν), καθώς δεν ανιχνεύσαμε ούτε αύξηση του πληθυσμού των προ-αποπτωτικών κυττάρων, ούτε και αύξηση της ενεργότητας του ενζύμου κασπάση-3. Παράλληλα, δεν προκλήθηκε σημαντική αλλαγή στα επίπεδα πρωτεϊνών που σχετίζονται με την απόπτωση εκτός από τις ακόλουθες πρωτεΐνες: ενεργή κασπάση-3, cIAP-2, Livin, catalase, p21, p27 και TRAIL R1 και R2 για το έλαιο της μαστίχας και τις survivin, claspin, TRAILR2, clusterin, HSP60 και Fas για το έλαιο της λουίζας, που μαζί με το citral πιθανόν να ενεργοποιούν το μονοπάτι της αυτοφαγίας βάσει πειραματικών ενδείξεων. Τέλος, η λουίζα διαθέτει μεγαλύτερη ικανότητα ενίσχυσης της δράσης των δύο χημειοθεραπευτικών παραγόντων oxaliplatin και irinotecan στις κυτταρικές σειρές Caco2 και HT-29 σε σχέση με το citral. Συμπερασματικά, τα ευρήματα μας υποδεικνύουν πως τα φυσικά εκχυλίσματα που μελετήσαμε, και κυρίως τα έλαια μαστίχας και λουίζας, διαθέτουν πολλά υποσχόμενες δραστικότητες που αξίζουν περαιτέρω διερεύνησης για τη μελλοντική χρήση τους ως χημειοπροληπτικοί και χημειοθεραπευτικοί παράγοντες.

A Novel Triazole Derivative Drug Presenting In Vitro and In Vivo Anticancer Properties

2018 ◽  
Vol 18 (17) ◽  
pp. 1483-1493
Author(s):  
Ricardo Imbroisi Filho ◽  
Daniel T.G. Gonzaga ◽  
Thainá M. Demaria ◽  
João G.B. Leandro ◽  
Dora C.S. Costa ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Cell Line ◽  
Cancer Cell ◽  
Cancer Cell Line ◽  
Hepatic Function ◽  
Anticancer Properties ◽  
Mcf 7

Background: Cancer is a major cause of death worldwide, despite many different drugs available to treat the disease. This high mortality rate is largely due to the complexity of the disease, which results from several genetic and epigenetic changes. Therefore, researchers are constantly searching for novel drugs that can target different and multiple aspects of cancer. Experimental: After a screening, we selected one novel molecule, out of ninety-four triazole derivatives, that strongly affects the viability and proliferation of the human breast cancer cell line MCF-7, with minimal effects on non-cancer cells. The drug, named DAN94, induced a dose-dependent decrease in MCF-7 cells viability, with an IC50 of 3.2 ± 0.2 µM. Additionally, DAN94 interfered with mitochondria metabolism promoting reactive oxygen species production, triggering apoptosis and arresting the cancer cells on G1/G0 phase of cell cycle, inhibiting cell proliferation. These effects are not observed when the drug was tested in the non-cancer cell line MCF10A. Using a mouse model with xenograft tumor implants, the drug preventing tumor growth presented no toxicity for the animal and without altering biochemical markers of hepatic function. Results and Conclusion: The novel drug DAN94 is selective for cancer cells, targeting the mitochondrial metabolism, which culminates in the cancer cell death. In the end, DAN94 has been shown to be a promising drug for controlling breast cancer with minimal undesirable effects.

scholarly journals Anticancer Activity of Triazolo-Thiadiazole Derivatives and Inhibition of AKT1 and AKT2 Activation

Pharmaceutics ◽  
2021 ◽  
Vol 13 (4) ◽  
pp. 493
Author(s):  
Dimitrios T. Trafalis ◽  
Sofia Sagredou ◽  
Panayiotis Dalezis ◽  
Maria Voura ◽  
Stella Fountoulaki ◽  
...  
Keyword(s):  
Anticancer Activity ◽  
Human Colon ◽  
Tumor Xenograft ◽  
Atp Binding Site ◽  
Anticancer Properties ◽  
Extensive Range ◽  
Dependent Inhibition ◽  
Ht 29

The fusion of 1,2,4-triazole and 1,3,4-thiadiazole rings results in a class of heterocycles compounds with an extensive range of pharmacological properties. A series of 1,2,4-triazolo[3,4-b]-1,2,4-thiadiazoles was synthesized and tested for its enzyme inhibition potential and anticancer activity. The results show that 1,2,4-triazolo[3,4-b]-1,2,4-thiadiazoles display potent anticancer properties in vitro against a panel of cancer cells and in vivo efficacy in HT-29 human colon tumor xenograft in CB17 severe combined immunodeficient (SCID) mice. Preliminary mechanistic studies revealed that KA25 and KA39 exhibit time- and concentration-dependent inhibition of Akt Ser-473 phosphorylation. Molecular modeling experiments indicated that 1,2,4-triazolo[3,4-b]-1,2,4-thiadiazoles bind well to the ATP binding site in Akt1 and Akt2. The low acute toxicity combined with in vitro and in vivo anticancer activity render triazolo[3,4-b]thiadiazoles KA25, KA26, and KA39 promising cancer therapeutic agents.

scholarly journals Thymoquinone, a Dietary Bioactive Compound, Exerts Anti-Inflammatory Effects in Colitis by Stimulating Expression of the Colonic Epithelial PPAR-γ Transcription Factor

Nutrients ◽  
2021 ◽  
Vol 13 (4) ◽  
pp. 1343
Author(s):  
Balaji Venkataraman ◽  
Saeeda Almarzooqi ◽  
Vishnu Raj ◽  
Abdullah T. Alhassani ◽  
Ahmad S. Alhassani ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Activity Index ◽  
Nigella Sativa ◽  
Mapk Signaling ◽  
Mitogen Activated Protein Kinase ◽  
Ppar Γ ◽  
Anti Inflammatory ◽  
Ht 29

Inflammatory bowel diseases (IBD) are chronic inflammatory disorders with increasing incidence and prevalence worldwide. Here, we investigated thymoquinone (TQ), a naturally occurring phytochemical present in Nigella sativa, for anti-inflammatory effects in colonic inflammation. To address this, we used in vivo (mice) and in vitro (HT-29 cells) models in this investigation. Our results showed that TQ treatment significantly reduced the disease activity index (DAI), myeloperoxidase (MPO) activity, and protected colon microscopic architecture. In addition, TQ also reduced the expression of proinflammatory cytokines and mediators at both the mRNA and protein levels. Further, TQ decreased phosphorylation of the activated mitogen-activated protein kinase (MAPK) signaling pathway and nuclear factor kappa B (NF-κB) proteins and enhanced colon epithelial PPAR-γ transcription factor expression. TQ significantly decreased proinflammatory chemokines (CXCL-1 and IL-8), and mediator (COX-2) mRNA expression in HT-29 cells treated with TNF-α. TQ also increased HT-29 PPAR-γ mRNA, PPAR-γ protein expression, and PPAR-γ promoter activity. These results indicate that TQ inhibits MAPK and NF-κB signaling pathways and transcriptionally regulates PPAR-γ expression to induce potent anti-inflammatory activity in vivo and in vitro models of colon inflammation.

scholarly journals Identification of the Active Ingredient and Beneficial Effects of Vitex rotundifolia Fruits on Menopausal Symptoms in Ovariectomized Rats

Biomolecules ◽  
2021 ◽  
Vol 11 (7) ◽  
pp. 1033
Author(s):  
Ji Hwan Lee ◽  
Sullim Lee ◽  
Quynh Nhu Nguyen ◽  
Hung Manh Phung ◽  
Myoung-Sook Shin ◽  
...  
Keyword(s):  
Weight Gain ◽  
Body Weight Gain ◽  
Animal Experiments ◽  
Ovariectomized Rats ◽  
Biological Functions ◽  
Menopausal Syndrome ◽  
Active Constituents ◽  
Mcf 7

Estrogen replacement therapy is a treatment to relieve the symptoms of menopause. Many studies suggest that natural bioactive ingredients from plants resemble estrogen in structure and biological functions and can relieve symptoms of menopause. The fruit of V. rotundifolia, called “Man HyungJa” in Korean, is a traditional medicine used to treat headache, migraine, eye pain, neuralgia, and premenstrual syndrome in Korea and China. The aim of the present study was to confirm that V. rotundifolia fruit extract (VFE) exerts biological functions similar to those of estrogen in menopausal syndrome. We investigated its in vitro effects on MCF-7 cells and in vivo estrogen-like effects on weight gain and uterine contraction in ovariectomized rats. Using the polar extract, the active constituents of VFE (artemetin, vitexicarpin, hesperidin, luteolin, vitexin, and vanillic acid) with estrogen-like activity were identified in MCF-7 cells. In animal experiments, the efficacy of VFE in ameliorating body weight gain was similar to that of estrogen, as evidenced from improvements in uterine atrophy. Vitexin and vitexicarpin are suggested as the active constituents of V. rotundifolia fruits.

In vitro evaluation of estrogenic, antiestrogenic and antitumor effects of amentoflavone

2021 ◽  
pp. 096032712199945
Author(s):  
AT Aliyev ◽  
S Ozcan-Sezer ◽  
A Akdemir ◽  
H Gurer-Orhan
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Antitumor Effects ◽  
Antiestrogenic Activity ◽  
Er Positive ◽  
In Vivo Effects ◽  
Mcf 7

Apigenin, a flavonoid, is reported to act as an estrogen receptor (ER) agonist and inhibit aromatase enzyme. However, amentoflavone, a biflavonoid bearing two apigenin molecules, has not been evaluated for its endocrine modulatory effects. Besides, it is highly consumed by young people to build muscles, enhance mood and lose weight. In the present study, apigenin was used as a reference molecule and ER mediated as well as ER-independent estrogenic/antiestrogenic activity of amentoflavone was investigated. Antitumor activity of amentoflavone was also investigated in both ER positive (MCF-7 BUS) and triple-negative (MDA-MB-231) breast cancer cells and its cytotoxicity was evaluated in human breast epithelial cells (MCF-10A). Our data confirmed ER agonist, aromatase inhibitory and cytotoxic effects of apigenin in breast cancer cells, where no ER mediated estrogenic effect and physiologically irrelevant, slight, aromatase inhibition was found for amentoflavone. Although selective cytotoxicity of amentoflavone was found in MCF-7 BUS cells, it does not seem to be an alternative to the present cytotoxic drugs. Therefore, neither an adverse effect, mediated by an estrogenic/antiestrogenic effect of amentoflavone nor a therapeutical benefit would be expected from amentoflavone. Further studies could be performed to investigate its in vivo effects.

scholarly journals Doxorubicin loaded magnetism nanoparticles based on cyclodextrin dendritic-graphene oxide inhibited MCF-7 cell proliferation

2021 ◽  
Vol 12 (1) ◽  
pp. 8-15
Author(s):  
Ainaz Mihanfar ◽  
Niloufar Targhazeh ◽  
Shirin Sadighparvar ◽  
Saber Ghazizadeh Darband ◽  
Maryam Majidinia ◽  
...  
Keyword(s):  
Graphene Oxide ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Anticancer Drug Delivery ◽  
Release Studies ◽  
Anti Cancer ◽  
Acidic Conditions ◽  
Mcf 7

Abstract Doxorubicin (DOX) is an effective chemotherapeutic agent used for the treatment of various types of cancer. However, its poor solubility, undesirable side effects, and short half-life have remained a challenge. We used a formulation based on graphene oxide as an anticancer drug delivery system for DOX in MCF-7 breast cancer cells, to address these issues. In vitro release studies confirmed that the synthesized formulation has an improved release profile in acidic conditions (similar to the tumor microenvironment). Further in vitro studies, including MTT, uptake, and apoptosis assays were performed. The toxic effects of the nanocarrier on the kidney, heart and liver of healthy rats were also evaluated. We observed that the DOX-loaded carrier improved the cytotoxic effect of DOX on the breast cell line compared to free DOX. In summary, our results introduce the DOX-loaded carrier as a potential platform for in vitro targeting of cancer cells and suggest further studies are necessary to investigate its in vivo anti-cancer potential.

scholarly journals Inhibition of MCF-7 breast cancer cell proliferation by 5alpha-dihydrotestosterone; a role for p21(Cip1/Waf1)

2004 ◽  
Vol 32 (3) ◽  
pp. 793-810 ◽  
Author(s):  
MA Greeve ◽  
RK Allan ◽  
JM Harvey ◽  
JM Bentel
Keyword(s):  
Breast Cancer ◽  
Cell Proliferation ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
S Phase ◽  
Cyclin D3 ◽  
P27 Kip1 ◽  
Mcf 7

Androgens inhibit the growth of breast cancer cells in vitro and in vivo by mechanisms that remain poorly defined. In this study, treatment of asynchronously growing MCF-7 breast cancer cells with the androgen, 5alpha-dihydrotestosterone (DHT), was shown to inhibit cell proliferation and induce moderate increases in the proportion of G1 phase cells. Consistent with targeting the G1-S phase transition, DHT pretreatment of MCF-7 cultures impeded the serum-induced progression of G1-arrested cells into S phase and reduced the kinase activities of cyclin-dependent kinase (Cdk)4 and Cdk2 to less than 50% of controls within 3 days. DHT treatment was associated with greater than twofold increases in the levels of the Cdk inhibitor, p27(Kip1), while p21(Cip1/Waf1) protein levels remained unchanged. During the first 24 h of DHT treatment, levels of Cdk4-associated p21(Cip1/Waf1) and p27(Kip1) were reduced coinciding with decreased levels of Cdk4-associated cyclin D3. In contrast, DHT treatment caused increased accumulation of Cdk2-associated p21(Cip1/Waf1), with no significant alterations in levels of p27(Kip1) bound to Cdk2 complexes. These findings suggest that DHT reverses the Cdk4-mediated titration of p21(Cip1/Waf1) and p27(Kip1) away from Cdk2 complexes, and that the increased association of p21(Cip1/Waf1) with Cdk2 complexes in part mediates the androgen-induced growth inhibition of breast cancer cells.

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