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PubMed2001

New responsibilities for the PI3K regulatory subunit p85 alpha.

Class IA phosphoinositide-3 kinases (PI3Ks) are heterodimeric enzymes that regulate many signal transduction pathways. The p85 regulatory subunit recruits the p110 catalytic subunit to the membrane, where p110 phosphorylates inositol lipids. Recent studies present evidence for an additional role for p85alpha in the regulation of actin cytoskeleton. Okkenhaug and Vanhaesebroeck discuss these results and ask whether experiments describing p85alpha knockout mice need to be reinterpreted.

Animals↗
PubMed2006

PI3K is involved in PDGF-beta receptor upregulation post-PDGF-BB treatment in mouse HSC.

Increased expression of PDGF-beta receptors is a landmark of hepatic stellate cell activation and transdifferentiation into myofibroblasts. However, the molecular mechanisms that regulate the fate of the receptor are lacking. Recent studies suggested that N-acetylcysteine enhances the extracellular degradation of PDGF-beta receptor by cathepsin B, thus suggesting that the absence of PDGF-beta receptors in quiescent cells is due to an active process of elimination and not to a lack of expression. In this communication we investigated further molecular mechanisms involved in PDGF-beta receptor elimination and reappearance after incubation with PDGF-BB. We showed that in culture-activated hepatic stellate cells there is no internal protein pool of receptor, that the protein is maximally phosphorylated by 5 min and completely degraded after 1 h by a lysosomal-dependent mechanism. Inhibition of receptor autophosphorylation by tyrphostin 1296 prevented its degradation, but several proteasomal inhibitors had no effect. We also showed that receptor reappearance is time and dose dependent, being more delayed in cells treated with 50 ng/ml (48 h) compared with 10 ng/ml (24 h).

Animals↗
PubMed2004

Cobalt induces hypoxia-inducible factor-1alpha expression in airway smooth muscle cells by a reactive oxygen species- and PI3K-dependent mechanism.

Cobalt can mimic hypoxia and has been implicated as a cause of lung defects. However, the effect of cobalt on airway smooth muscle (ASM) cells has not been analyzed in detail. In this article, we use primary cultures of ASM cells from rabbit trachea and show that exposure to cobalt chloride causes a rapid increase of the intracellular levels of hypoxia-inducible factor-1alpha, which is detected predominantly inside the nucleus. With the use of specific inhibitors, we demonstrate that induction of hypoxia-inducible factor-1alpha by cobalt depends on active protein synthesis but not transcription. Furthermore, wortmannin, LY294002, and N-acetyl-L-cysteine inhibit the effect of cobalt, suggesting that it involves the phosphatidylinositol 3 kinase pathway and production of reactive oxygen species. Interestingly, cobalt chloride attenuates the contractile response of rabbit airways induced by potassium chloride, but not by acetylcholine, suggesting a link between the cellular response to hypoxic stimuli and the contractile properties of ASM cells.

Acetylcysteine↗
PubMed2006

DC-SIGN ligation on dendritic cells results in ERK and PI3K activation and modulates cytokine production.

The generation of pathogen-specific immune responses is dependent on the signaling capabilities of pathogen-recognition receptors. DC-SIGN is a C-type lectin that mediates capture and internalization of viral, bacterial, and fungal pathogens by myeloid dendritic cells. DC-SIGN-interacting pathogens are thought to modulate dendritic cell maturation by interfering with intracellular signaling from Toll-like receptor molecules. We report that engagement of DC-SIGN by specific antibodies does not promote dendritic cell maturation but induces ERK1/2 and Akt phosphorylation without concomitant p38MAPK activation. DC-SIGN ligation also triggers PLCgamma phosphorylation and transient increases in intracellular calcium in dendritic cells. In agreement with its signaling capabilities, a fraction of DC-SIGN molecules partitions within lipid raft-enriched membrane fractions both in DC-SIGN-transfected and dendritic cells. Moreover, DC-SIGN in dendritic cells coprecipitates with the tyrosine kinases Lyn and Syk. The relevance of the DC-SIGN-initiated signals was demonstrated in monocyte-derived dendritic cells, as DC-SIGN cross-linking synergizes with TNF-alpha for IL-10 release and enhances the production of LPS-induced IL-10. These results demonstrate that DC-SIGN-triggered intracellular signals modulate dendritic cell maturation. Since pathogens stimulate Th2 responses via preferential activation of ERK1/2, these results provide a molecular explanation for the ability of DC-SIGN-interacting pathogens to preferentially evoke Th2-type immune responses.

Antigens, CD↗
PubMed2006

PI3K signaling and miRNA expression during the response of quiescent human fibroblasts to distinct proliferative stimuli.

BACKGROUND: Serum treatment of quiescent human dermal fibroblasts induces proliferation, coupled with a complex physiological response that is indicative of their normal role in wound-healing. However, it is not known to what extent such complex transcriptional events are specific to a given cell type and signal, and how these global changes are coordinately regulated. We have profiled the global transcriptional program of human fibroblasts from two different tissue sources to distinct growth stimuli, and identified a striking conservation in their gene-expression signatures. RESULTS: We found that the wound-healing program of gene expression was not specific to the response of dermal fibroblasts to serum but was regulated more broadly. However, there were specific differences among different stimuli with regard to signaling pathways that mediate these transcriptional programs. Our data suggest that the PI3-kinase pathway is differentially involved in mediating the responses of cells to serum as compared with individual peptide growth factors. Expression profiling indicated that let7 and other miRNAs with similar expression profiles may be involved in regulating the transcriptional program in response to proliferative signals. CONCLUSION: This study provides insights into how different stimuli use distinct as well as conserved signaling and regulatory mechanisms to mediate genome-wide transcriptional reprogramming during cell proliferation. Our results indicate that conservation of transcriptional programs and their regulation among different cell types may be much broader than previously appreciated.

Cell Line↗
PubMed2006

The RNA-binding protein KSRP promotes decay of beta-catenin mRNA and is inactivated by PI3K-AKT signaling.

Beta-catenin plays an essential role in several biological events including cell fate determination, cell proliferation, and transformation. Here we report that beta-catenin is encoded by a labile transcript whose half-life is prolonged by Wnt and phosphatidylinositol 3-kinase-AKT signaling. AKT phosphorylates the mRNA decay-promoting factor KSRP at a unique serine residue, induces its association with the multifunctional protein 14-3-3, and prevents KSRP interaction with the exoribonucleolytic complex exosome. This impairs KSRP's ability to promote rapid mRNA decay. Our results uncover an unanticipated level of control of beta-catenin expression pointing to KSRP as a required factor to ensure rapid degradation of beta-catenin in unstimulated cells. We propose KSRP phosphorylation as a link between phosphatidylinositol 3-kinase-AKT signaling and beta-catenin accumulation.

14-3-3 Proteins↗
PubMed2006

Ghrelin and unacylated ghrelin stimulate human osteoblast growth via mitogen-activated protein kinase (MAPK)/phosphoinositide 3-kinase (PI3K) pathways in the absence of GHS-R1a.

Recent studies demonstrate widespread expression of ghrelin among tissues and have uncovered its pleiotropic nature. We have examined gene expression of ghrelin and its two receptor splice variants, growth hormone secretagogue receptors (GHS-R) 1a and 1b, in human bone biopsies and in the human pre-osteoblastic SV-HFO cell line during differentiation. Additionally, we examined proliferative effects of ghrelin and unacylated ghrelin (UAG) in differentiating and non-differentiating cells. We detected GHS-R1b mRNA in human bone and osteoblasts but not ghrelin's cognate receptor GHS-R1a, using two different real-time PCR assays and both total RNA and mRNA. In osteoblasts GHS-R1b mRNA expression remained low during the first 14 days of culture, but increased 300% in differentiating cells by day 21. Both human bone biopsies and osteoblasts expressed ghrelin mRNA, and osteoblasts were found to secrete ghrelin. Overall, ghrelin gene expression was greater in differentiating than non-differentiating osteoblasts, but was not increased during culture in either group. Ghrelin and UAG induced thymidine uptake dose-dependently, peaking at 1 and 10 nM respectively, at day 6 of culture in both non-differentiating and differentiating osteoblasts. The proliferative response to ghrelin and UAG declined with culture time and state of differentiation. The proliferative effects of ghrelin and UAG were suppressed by inhibitors of extracellular-signal-regulated kinase (ERK) and phosphoinositide-3 kinase, and both peptides rapidly induced ERK phosphorylation. Overall, our data suggest new roles for ghrelin and UAG in modulating human osteoblast proliferation via a novel signal transduction pathway.

Alkaline Phosphatase↗
PubMed2006

Avoidance of Abeta[(25-35)] / (H(2)O(2)) -induced apoptosis in lymphocytes by the cannabinoid agonists CP55,940 and JWH-015 via receptor-independent and PI3K-dependent mechanisms: role of NF-kappaB and p53.

Cannabinoids have been suggested as potential neuroprotective compounds in Alzheimer's disease (AD). Despite intense investigation, the detailed intracellular mechanism(s) involved in cannabinoids survival effect remains to be elucidated. The present study shows that CP55,940 (a CB1 and CB2 agonist) and JWH-015 (a CB2 agonist) protect and rescue peripheral blood lymphocytes (PBL) from (10 microM) Abeta[(25-35)] and (50 microM) H(2)O(2)-induced apoptosis by two alternative mechanisms: (1) receptor-independent pathway, as demonstrated by no-dihydrorhodamine oxidation into fluorescent rhodamine 123 (R-123) as a result of cannabinoid inhibition of Abeta-generated H(2)O(2); (2) receptor-dependent pathway through NF-kappaB activation and p53 down regulation involving phosphoinositide 3-kinase (PI-3K), as demonstrated by using either (25 microM) LY294002 (a PI-3K inhibitor), (50 nM) pifithrin-alpha (PFT, a specific p53 inhibitor) or by using immunocytochemistry detection of NF-kappaB and p53 transcription factors activation. Importantly, cannabinoid agonists and PFT were able to protect and rescue lymphocytes pre-exposed to toxicants-, even when the three compounds were added up-to 12 h post-Abeta[(25-35)]/(H(2)O(2)) exposure. These results suggest that CP55,940/( JWH-015) protection/rescue of PBL from noxious stimuli is determined by p53 inactivation. These findings may contribute to a better understanding of the role played by cannabinoids as neuroprotective agents to target and interrupt molecular signaling that induce damage in AD disorder.

Adult↗
PubMed2005

Effects of MEK1 and PI3K inhibitors on allyl-, benzyl- and phenylethyl-isothiocyanate-induced G2/M arrest and cell death in Caco-2 cells.

Isothiocyanates (ITCs) are potentially important cancer chemopreventive compounds found in cruciferous vegetables. In this study, three ITCs: allyl ITC, benzyl ITC and phenylethyl ITC, induced DNA cell-cycle changes and cell death in undifferentiated Caco-2 cells and their roles in PI3K/Akt and MEK/ERK signaling pathways have been investigated. Flow cytometric analysis was used to measure cell-cycle distribution, expression of mitotic marker (phosphorylated H3 histone), mitochondrial transmembrane potential for the determination of ITC-induced apoptosis measured by Annexin V-FITC staining and metabolic conversion of fluorescein diacetate, and quantification of sub-G1 population. Cellular MAPK and phosphorylated MAPK were measured using western blot analysis. All ITCs tested induced G2/M cell-cycle arrest after 24-h treatment, a time- and concentration-dependent activation of ERK1/2, dissipation of mitochondrial transmembrane potential and apoptosis. Both PI3K/Akt and MEK/ERK inhibitors, LY294002 and PD98059, attenuated the extent of BITC-induced cell death. Pretreatment of cells with either the PD98059 or LY294002 inhibitor, caused a dose-dependent inhibition of histone H3 (p-H3) phosphorylation. Despite the LY294002 inhibitor having no effect on the proportion of ITC-induced G2/M arrested cells, a significant decrease of p-H3/(G2/M) ratio in both PD98059- and LY294002-treated cells was observed. We suggest that the decrease of mitotic cells was compensated for by an increase of cells in G2 phase. LY294002 and PD98059 affect cell transition from G2 to M phase and from S to G2 phase respectively. These results indicate that isothiocyanates can induce cell cycle-change through multiple signaling pathways and more detailed study is merited to further unravel the chemopreventive and chemotherapeutic mechanisms of ITCs.

Apoptosis↗
PubMed1996

Platelet-derived growth factor-dependent activation of phosphatidylinositol 3-kinase is regulated by receptor binding of SH2-domain-containing proteins which influence Ras activity.

Upon binding of platelet-derived growth factor (PDGF), the PDGF beta receptor (PDGFR) undergoes autophosphorylation on distinct tyrosine residues and binds several SH2-domain-containing signal relay enzymes, including phosphatidylinositol 3-kinase (PI3K), phospholipase C gamma (PLC gamma), the GTPase-activating protein of Ras (RasGAP), and the tyrosine phosphatase SHP-2. In this study, we have investigated whether PDGF-dependent PI3K activation is affected by the other proteins that associate with the PDGFR. We constructed and characterized a series of PDGFR mutants which contain binding sites for PI3K as well as one additional protein, either RasGAP, SHP-2, or PLC gamma. While all of the receptors had wild-type levels of PDGF-stimulated tyrosine kinase activity and associated with comparable amounts of PI3K activity, their abilities to trigger accumulation of PI3K products in vivo differed dramatically. The wild-type receptor, as well as receptors that recruited PI3K or PI3K and SHP-2, were all capable of fully activating PI3K. In contrast, receptors that associated with PI3K and RasGAP or PI3K and PLC gamma displayed a greatly reduced ability to stimulate production of PI3K products. When this series of receptors was tested for their ability to activate Ras, we observed a strong positive correlation between Ras activation and PI3K activation. Further investigation of the relationship between Ras and PI3K indicated that Ras was upstream of PI3K. Thus, activation of PI3K requires not only binding of PI3K to the tyrosine-phosphorylated PDGFR but accumulation of GTP-bound Ras as well. Furthermore, PLC gamma and RasGAP negatively modulate PDGF-dependent PI3K activation. Finally, PDGF-stimulated signal relay can be regulated by altering the ratio of SH2-domain-containing enzymes that are recruited to the PDGFR.

3T3 Cells↗
PubMed2000

Class II phosphoinositide 3-kinases are downstream targets of activated polypeptide growth factor receptors.

The class II phosphoinositide 3-kinases (PI3K) PI3K-C2alpha and PI3K-C2beta are two recently identified members of the large PI3K family. Both enzymes are characterized by the presence of a C2 domain at the carboxy terminus and, in vitro, preferentially utilize phosphatidylinositol and phosphatidylinositol 4-monophosphate as lipid substrates. Little is understood about how the catalytic activity of either enzyme is regulated in vivo. In this study, we demonstrate that PI3K-C2alpha and PI3K-C2beta represent two downstream targets of the activated epidermal growth factor (EGF) receptor in human carcinoma-derived A431 cells. Stimulation of quiescent cultures with EGF resulted in the rapid recruitment of both enzymes to a phosphotyrosine signaling complex that contained the EGF receptor and Erb-B2. Ligand addition also induced the appearance of a second, more slowly migrating band of PI3K-C2alpha and PI3K-C2beta immunoreactivity on sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Since both PI3K enzymes can utilize Ca(2+) as an essential divalent cation in lipid kinase assays and since the catalytic activity of PI3K-C2alpha is refractory to the inhibitor wortmannin, these properties were used to confirm the recruitment of each PI3K isozyme to the activated EGF receptor complex. To examine this interaction in greater detail, PI3K-C2beta was chosen for further investigation. EGF and platelet-derived growth factor also stimulated the association of PI3K-C2beta with their respective receptors in other cells, including epithelial cells and fibroblasts. The use of EGF receptor mutants and phosphopeptides derived from the EGF receptor and Erb-B2 demonstrated that the interaction with recombinant PI3K-C2beta occurs through E(p)YL/I phosphotyrosine motifs. The N-terminal region of PI3K-C2beta was found to selectively interact with the EGF receptor in vitro, suggesting that it mediates the association of this PI3K with the receptor. However, the mechanism of this interaction remains unclear. We conclude that class II PI3K enzymes may contribute to the generation of 3' phosphoinositides following the activation of polypeptide growth factor receptors in vivo and thus mediate certain aspects of their biological activity.

Binding Sites↗
PubMed2000

Involvement of phosphoinositide 3-kinase and its association with pp60src in cholecystokinin-stimulated pancreatic acinar cells.

Phosphoinositide 3-kinase (PI3K) is a lipid kinase which phosphorylates the D3 position of the phosphoinositide derivatives and is known to be activated by a host of protein tyrosine kinases. PI3K has been demonstrated to play an important role in mitogenesis and cell transformation in several cell systems. However, the functional roles of PI3K in pancreatic acinar cells remain to be determined. The objective of this study was to identify and characterize the PI3K pathway and its relation to other non-receptor protein tyrosine kinases in mediating signal transduction of pancreatic acinar cells. Intact acini isolated from the rat pancreas were incubated with or without cholecystokinin octapeptide (CCK-8). A Triton X-100-soluble and 10000 rpm supernatant of the cell sonicates was used for immunoprecipitation and Western immunoblotting. When a monoclonal anti-phosphotyrosine antibody (clone 4G10) was used, two major tyrosine-phosphorylated bands were observed at the location of p85 and p60. CCK (10 pM and 10 nM) significantly enhanced the tyrosine phosphorylation of these two bands. Furthermore, when a monoclonal anti-PI3K antibody (clone UB93-3) which recognizes the N-terminal SH2 domain of the p85 regulatory subunit of PI3K was used, CCK (10 pM-10 nM) dose-dependently increased the amount of the immunodetectable PI3K band with a peak occurring at 5 min. The increase in the immunodetectable PI3K band elicited by CCK did not require the presence of extracellular Ca2+. The pp60src inhibitor, herbimycin A (6 microM), and the PI3K inhibitor, wortmannin (6 microM), both decreased intensities of the PI3K band elicited by CCK. Herbimycin A abolished phosphotransferase activities of the Src kinase following stimulation with CCK, whereas wortmannin had no effect, suggesting that Src is an upstream regulator of PI3K. Wortmannin (3-6 microM) abolished CCK-stimulated pancreatic amylase secretion. Immunoprecipitation studies using an anti-Src antibody (clone CD11) or PI3K antibody in conjunction with the anti-phosphotyrosine antibody showed that, in response to CCK, tyrosine phosphorylations of Src and PI3K were enhanced at the location of p60 and p85, respectively. Src was co-immunoprecipitated with PI3K following stimulation with CCK, suggesting that pp60src forms an immunocomplex with PI3K via the N-SH2 domain of the p85 regulatory subunit. Thus PI3K and its association with Src appear to be involved in mediating CCK-stimulated pancreatic exocytosis.

Amylases↗
PubMed2002

Involvement of PI3-kinase and its association with c-Src in PTH-stimulated rat enterocytes.

Phosphoinositide-3-kinase (PI3K) is a lipid kinase, which phosphorylates the D3 position of phosphoinositides, and is known to be activated by a host of protein tyrosine kinases. PI3K plays an important role in mitogenesis in several cell systems. However, whether parathyroid hormone (PTH) affects the activity and functional roles of PI3K in intestinal cells remain to be determined. The objective of this study was to identify and characterize the PI3K pathway, and its relation to other non-receptor tyrosine kinases in mediating PTH signal transduction in rat enterocytes. PTH dose- and time-dependently increased PI3K activity with a peak occurring at 2 min. The tyrosine kinase inhibitor genistein, c-Src inhibitor PP1 and two structurally different inhibitors of PI3K, LY294002 and wortmannin, suppressed PI3K activity dependent on PTH. Co-immunoprecipitation analysis showed a constitutive association between c-Src and PI3K, which was enhanced by PTH treatment, suggesting that the cytosolic tyrosine kinase forms an immunocomplex with PI3K probably via the N-SH2 domain of the p85alpha regulatory subunit. In response to PTH, tyrosine phosphorylation of p85alpha was enhanced, effect that was abolished by PP1, the inhibitor of c-Src kinase. PTH causes a rapid (0.5-5 min) phosphorylation of Akt/PKB, effect that was abrogated by PI3K inhibitors, indicating that in rat enterocytes, PI3K is an upstream mediator of Akt/PKB activation by PTH. We report here that PI3K is also required for PTH activation of the mitogen-activated protein kinases ERK1 and ERK2. Taken together, the present study demonstrate, for the first time, that PTH rapidly and transiently stimulates PI3K activity and its down effector Akt/PKB in rat enterocytes playing c-Src kinase a central role in PTH-dependent PI3K activation and that PI3K signaling pathway contributes to PTH-mediated MAPK activation.

Animals↗
PubMed1993

Specific activity of phosphatidylinositol 3-kinase is increased by insulin stimulation.

We investigated whether phosphatidylinositol 3-kinase (PI3K) is phosphorylated and whether its specific activity is increased by insulin stimulation in vivo using Fao cells and antibodies raised against the 85 kDa subunit of PI3K, insulin-receptor substrate-1 (IRS-1), and phosphotyrosine (pTyr). PI3K activity was detected in the immunoprecipitate produced with anti-PI3K at a basal state. The activity was increased 2-3-fold by insulin stimulation, although the protein concentration of kinase in the anti-PI3K immunoprecipitates was the same before and after insulin stimulation. Both anti-pTyr and anti-IRS-1 antibodies immunoprecipitated the kinase activity only after insulin stimulation. After the first immunoprecipitation with anti-pTyr, the supernatant was immunoprecipitated once more with anti-PI3K. PI3K activity in the second immunoprecipitate revealed little difference between the basal and insulin-stimulated states, suggesting that most of the insulin-activated portion of PI3K was precipitated by anti-pTyr. Both IRS-1 and the insulin-receptor beta-subunit (95 kDa) were phosphorylated on tyrosine residues by insulin stimulation and immunoprecipitated with anti-pTyr. However, phosphorylation of neither subunit of PI3K (85 kDa or 110 kDa) was detectable in the immunoprecipitate produced with anti-pTyr. The 185 kDa pTyr-containing protein was immunoprecipitated with anti-PI3K after insulin stimulation, although there was little phosphorylation of the 85 kDa protein. pTyr in the 110 kDa protein immunoprecipitated with anti-PI3K was below detectable levels. These results indicate that the specific activity of PI3K is increased by insulin stimulation without detectable tyrosine phosphorylation of PI3K itself in Fao cells. The majority of the insulin-activated portion of PI3K is associated with pTyr-containing proteins including IRS-1, which suggests that this is important for activation of PI3K by insulin.

Animals↗
PubMed2006

Antitumor activity of ZSTK474, a new phosphatidylinositol 3-kinase inhibitor.

BACKGROUND: We previously synthesized a novel s-triazine derivative, ZSTK474 [2-(2-difluoromethylbenzimidazol-1-yl)-4,6-dimorpholino-1,3,5-triazine], that strongly inhibited the growth of tumor cells. We identified its molecular target, investigated its effects on cellular signaling pathways, and examined its antitumor efficacy and toxicity in vivo. METHODS: We used COMPARE analysis of chemosensitivity measurements from 39 human cancer cell lines and identified phosphatidylinositol 3-kinase (PI3K) as a molecular target for ZSTK474. PI3K was immunoprecipitated from A549 cell lysates, and its activity was measured by assessing the incorporation of 32P into phosphatidylinositol. We used the crystal structure of the PI3K-LY294002 complex to model the binding of ZSTK474 to PI3K (where LY294002 is a known PI3K inhibitor). PI3K downstream activity was analyzed by immunoblotting. Antitumor activity of ZSTK474 was examined against A549, PC-3, and WiDr xenografts in nude mice. Phosphorylation of Akt, a serine/threonine protein kinase and a major signaling component downstream of PI3K, was assessed in vivo by immunohistochemistry. RESULTS: PI3K was identified as a molecular target for ZSTK474 by COMPARE analysis. We confirmed that ZSTK474 directly inhibited PI3K activity more efficiently than the PI3K inhibitor LY294002. At concentrations of 1 microM, ZSTK474 and LY2194002 reduced PI3K activity to 4.7% (95% confidence interval [CI] = 3.2% to 6.1%) and 44.6% (95% CI = 38.9% to 50.3%), respectively, of the untreated control level. Molecular modeling of the PI3K-ZSTK474 complex indicated that ZSTK474 could bind to the ATP-binding pocket of PI3K. ZSTK474 inhibited phosphorylation of signaling components downstream from PI3K, such as Akt and glycogen synthase kinase 3beta, and mediated a decrease in cyclin D1 levels. ZSTK474 administered orally to mice had strong antitumor activity against human cancer xenografts without toxic effects in critical organs. Akt phosphorylation was reduced in xenograft tumors after oral administration of ZSTK474. CONCLUSION: ZSTK474 is a new PI3K inhibitor with strong antitumor activity against human cancer xenografts without toxic effects in critical organs. ZSTK474 merits further investigation as an anticancer drug.

Androstadienes↗