WO2013097017A1 - Compositions pharmaceutiques contenant de l'ang-(1-7) ou un autre agoniste du récepteur mas avec inhibiteurs de pi3k/akt pour le traitement thérapeutique anticancer - Google Patents

Compositions pharmaceutiques contenant de l'ang-(1-7) ou un autre agoniste du récepteur mas avec inhibiteurs de pi3k/akt pour le traitement thérapeutique anticancer Download PDF

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WO2013097017A1
WO2013097017A1 PCT/BR2012/000556 BR2012000556W WO2013097017A1 WO 2013097017 A1 WO2013097017 A1 WO 2013097017A1 BR 2012000556 W BR2012000556 W BR 2012000556W WO 2013097017 A1 WO2013097017 A1 WO 2013097017A1
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pi3k
pharmaceutical compositions
ang
akt
receptor agonist
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Portuguese (pt)
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Robson Augusto Souza Dos Santos
Danielle GOMES PASSOS SILVA
Frederic JEAN GEORGES FREZARD
Thiago VERANO BRAGA
Peter Roepstorff
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Universidade Federal De Minas Gerais - Ufmg
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/08—Peptides having 5 to 11 amino acids
    • A61K38/085—Angiotensins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis

Definitions

  • the present invention describes pharmaceutical compositions containing a combination of Ang- (1-7) or other Mas receptor agonist with PI3K / Akt inhibitors for anticancer therapeutic treatment.
  • the combination of Ang- (1-7) and PI3K / Akt inhibitors results in inhibition of cancer progression by inhibiting cell growth or proliferation or activating apoptosis cell death in mammals, particularly humans.
  • Angiotensin- (1-7) is an endogenous heptapeptide, a component of the renin-angiotensin system. This peptide is generated primarily by the cleavage of angiotensin II (Ang II) by the angiotensin converting enzyme 2 (ACE2) (Tipnis SR et al., 2000. A human homolog of angiotensin-converting enzyme. Cloning and functional expression as a captopril- insensitive carboxypeptidase J Biol Chem Oct 27; 275 (43): 33238-43 PubMed PMID: 10924499; Santos RA et al., 2008. Recent advances in the angiotensin-converting enzyme 2-angiotensin (1-7) -But Axis Exp Physiol May 93 (5): 519-27 Epub 2008 Feb 29. Review PubMed PMID 18310257).
  • Ang- (1-7) counteracts the physiological effects of Ang II, such as vasoconstriction, through its binding to the G protein-coupled Mas receptor.
  • Ang- (1-7) agonists capable of activating the Mas receptor have recently been described, some of which are called CGEN-856S, CGEN-857 and AVE0991 (Santos RA et al., 2003.
  • Angiotensin- (1-7 ) is an endogenous ligand for the G protein-coupled Mas receptor Proc Natl Acad Sci USA Jul 8; 100 (14): 8258-63 Epub 2003 Jun 26.
  • the kallikrein-kinin and the renin-angiotensin systems have a multilayered interaction Am J Physiol Regul Integr Comp Physiol. Jul; 285 (1): R1-13.
  • Ang- (1-7) plays a central role in regulating blood pressure and improving cardiac function through antiarrhythmic, antihypertrophic and antifibrotic action. In addition to these roles, Ang- (1-7) has antiangiogenic action through inhibition of vascular growth and antimitogenic action, as exemplified by inhibition of lung cancer cell proliferation. Thus, Ang- (1-7) has a great potential for inhibition of tumor growth, as even experimentally demonstrated in patients (Santos RA, Frézard F, Ferreira AJ, 2005. Angiotensin- (1-7) : blood, heart, and blood vessels Curr Med Chem Cardiovasc Hematol Agents Oct; 3 (4): 383-91 Review PubMed PMID: 16250869; Schindler C et al., 2007.
  • PubMed PMID 1 1247819; Gallagher PE et al., 2011. Angiotensin peptides and lung cancer. Curr Cancer Drug Targets. May; 11 (4): 394-404. PubMed PMID: 21395552; Tallant EA, Clark MA, 2003. Molecular mechanisms of inhibition of vascular growth by angiotensin (1-7). Hypertension 2003 Oct; 42 (4): 574-9. Epub 2003 Sep 2. PubMed PMID: 12953014; Gallagher PE, Tallant EA, 2004. Inhibition of human lung cancer cell growth by angiotensin (1-7). Carcinogenesis. Nov; 25 (11): 2045-52.
  • PubMed PMID 15284177; Rodgers et al., 2006. Phase III dose escalation study of angiotensin 1-7 [A (1-7)] administered before and after chemotherapy in patients with newly diagnosed breast cancer. Cancer Chemother Pharmacol. May; 57 (5): 559-68. Epub 2005 Aug 12. PubMed PMID: 16096787, Soto-Pantoja DR et al, 2009. Angiotensin- (1-7) inhibits tumor angiogenesis in human lung cancer xenografts with a reduction in vascular endothelial growth factor. Mol Cancer Ther. Jun; 8 (6): 1676-83. Epub 2009 Jun 9. PubMed PMID: 19509262).
  • PI3K phosphatidylinositol-3 kinase
  • PI3K and / or Akt inhibitors include, but are not limited to, wortmannin, LY294002, FTY720, UCN-01, celecoxib and analogs thereof, such as OSU-03012 and OSU-03013, Akt-1-1, Akt-1- 1, 2 and API-2 (Yano, H et al., J.
  • US 2008167251 entitled “Angiotensin- (1-7) and Angiotensin- (1-7) Agonists for Inhibition of Cancer Celi Growth” describes the use of Ang- (1-7) or Ang- (1) receptor agonists. -7) in non-limiting compositions for the treatment of breast and lung cancer.
  • WO 2005046678 entitled “Cancer treatment method” describes pharmaceutical combinations and method for treating cancer including administration of an erb family inhibitor and a PI3K and / or Akt inhibitor.
  • WO 2005110477 entitled “Combination therapies for cancer and proliferative angiopathies” describes compositions and methods for treating cancer and proliferative angiopathies including a Jak2 / Stat3 signaling pathway inhibitor and a PI3K / Akt signaling pathway inhibitor.
  • WO 2010037892 entitled “Composition comprising silibinin at determined concentrations and combined preparation comprising silibinin and a PI3K / A pathway inhibitor for the treatment of cancer" describes the use of a composition comprising silibinin or alternatively silibinin is an Akt inhibitor for the preparation of a cancer treatment medicament, and a combined preparation of at least silibinin and a PI3K / Akt inhibitor for use separately, simultaneously or sequentially in cancer treatment.
  • compositions containing PI3K / Akt inhibitors in combination with Mas receptor agonists, preferably Ang- (1-7), for treating neoplasms as described in the present invention.
  • Figure 1 shows the time-dependent (de) phosphorylation profile grouping. This figure describes the results of the fuzzy c-means grouping procedure. The groupings were divided into four main groups based on phosphorylation kinetics. Phosphosite-containing proteins with cluster values greater than 0.3 are shown below each cluster
  • Figure 2 shows the percentage survival of tumor cells when treated with the combination of Angiotensin 1-7 (10 "6 ) and PI3K inhibitors (wortmannin and LY294002) relative to untreated cells.
  • Figure 3 shows the localization of FoxO1 in A549 tumor cells by immunofluorescence before (A) and after treatment with angiotensin 1-7 (10 "7 ) (B). Cells were labeled with DAPI and anti-antibodies. -FoxO1 (Cellsignalling) detected with Alexa 488 conjugated rabbit anti-IgG. DETAILED DESCRIPTION OF TECHNOLOGY
  • the present invention describes anticancer pharmaceutical compositions, characterized in that they comprise Mas receptor agonists, preferably Angiotensin- (1-7), in combination with PI3K / Akt inhibitors and pharmaceutically acceptable excipients.
  • Mas receptor agonists preferably Angiotensin- (1-7
  • compositions are selected from a group comprising water, saline, phosphate buffered solutions, Ringer's solution, dextrose solution, Hank's solution, biocompatible saline solutions containing or not polyethylene glycol, non-aqueous vehicles such as fixed oils, oil sesame, ethyl oleate or triglycerides, alone or in admixture, including nanopreparations; may contain additives such as buffers, preservatives, binders, disintegrants, diluents, lubricants and / or surfactants.
  • the Mas receptor agonist and PI3K / Akt inhibitors may be administered simultaneously or within 10 minutes of each other.
  • the Mas receptor agonist and PI3K / Akt inhibitors may be administered in a formulation comprising cyclodextrins, cyclodextrin derivatives, liposomes, biodegradable polymers, biodegradable polymer derivatives or mixtures thereof; They may be presented in solid, semi-solid or liquid form; and may be administered orally, intramuscularly, intravenously, intraperitoneally, subcutaneously, transdermally or as devices that may be implanted or injected.
  • the Mas receptor agonist and PI3K / Akt inhibitors may be administered using the same or different forms of application.
  • compositions of the present invention may be used to prepare a medicament for treating individuals with neoplasia.
  • the present invention demonstrates that treatment of endothelial cells with Ang- (1-7) alters the phosphorylation state of some components of the PI3K / Akt signaling pathway and various proteins involved in anti-tumorigenic processes, such as regulation of cell proliferation. and angiogenesis. It also demonstrates that anti-cancer treatment using Ang- (1-7) may have a more significant effect when used in conjunction with PI3K / Akt pathway inhibitors.
  • FoxOI a key protein in controlling cell proliferation and targeting of the PI3K / AKT pathway and angiotensin 1-7-triggered signaling cascade, was performed by immunofluorescence in tumor cells.
  • Example 1 Endothelial cell stimulation with Ang- (1-7), peptide acquisition, peptide labeling, and phosphopeptide enrichment
  • the cells were lysed to protein extraction using 400 ⁇ _ of a solution containing 7M urea; 2M thiourea; 200mM triethylammonium bicarbonate; 0.05% RapiGest TM (Waters - Milford, USA); 0.1M pervanadate; protease and phosphatase inhibitor cocktails (Roche - Mannheim, Germany)]
  • a solution containing 7M urea; 2M thiourea; 200mM triethylammonium bicarbonate; 0.05% RapiGest TM Waters - Milford, USA
  • 0.1M pervanadate protease and phosphatase inhibitor cocktails
  • the peptides (100 g) were labeled with iTRAQ ® reagents (Applied Biosystems - Foster City, USA), and combined at a ratio of 1: 1: 1: 1. Subsequently, the phosphopeptides present in the sample were enriched using TiO 2 and SIMAC (Larsen, MR et al., 2005. Highly selective enrichment of phosphorylated peptides from peptide mixtures using titanium dioxide microcolumns. Molecular & cellular proteomics: MCP 4, 873- 886; Thingholm, TE et al., 2008. SIMAC (sequential elution from IMAC), a phosphoproteomics strategy for the rapid separation of monophosphorylated from multiply phosphorylated peptides. Mol Celi Proteomics 7, 661-671).
  • the enriched phosphopeptides were resuspended in 0.1% formic acid (FA) and purified by reverse phase liquid chromatography on a 17 cm X 100 m column.
  • Reprosil-Pur C18-AQ (3 ⁇ ; Dr. Maisch GmbH - Ammerbuch, Germany) using an Easy-LC nanoHPLC (Proxeon - Odense, Denmark).
  • the gradient of chromatography was 0-34% solvent B (90% ACN, 0.1% FA) for 200 min at a flow rate of 250 nL / min.
  • the LTQ-Orbitrap XL instrument (Thermo Fisher - Waltham, USA) was operated in a positive mode and using multistage activation (MSA) for MSMS fragmentation (Schroeder, MJ et al., 2004).
  • MSA multistage activation
  • a neutral loss activation method for improved phosphopeptide sequence analysis by quadrupole ion trap mass spectrometry (Analytical chemistry 76, 3590-3598). In total, 2243 single phosphopeptides with 99% confidence (1% FDR) were identified.
  • MS / MS spectra were searched in the human sequence library database in the protein sequence database (Sprot 2010_ 2 version: 523,151 sequences; 184,678,199 residues) using an in-house Mascot server (version 2.2.04, Matrix Science Ltd. - London, UK).
  • ADAM9 Q 13443 Disintegrin and metalloproteinase domain-containing protein 9 precursor * S758, * T761
  • AKAP12 Q02952 A-kinase anchor protein 12 isoform 1 * S696, * S697, * S698
  • ANP32B Q92688 Acidic leucine-rich nuclear phosphoprotein 32 family member B * T244
  • EIF5B 060841 Eukaryotic translation initiation factor 5B * S214
  • HNRNPA3 P51991 Heterogeneous nuclear ribonucleoprotein A3 * Y360
  • HNRNPC P07910 Heterogeneous nuclear ribonucleoproteins C1 / C2 isoform a * S233
  • HNRNPH1 P31943 Heterogeneous nuclear ribonucleoprotein H * S104
  • MAP4 P27816 Microtubule-associated protein 4 isoform 1 * S787, * S1073 MAPK1 P28482 Mitogen-activated protein kinase 1 * Y187
  • TJP2 Q9UDY2 Tight junction protein ZO-2 isoform 1 * S130, * S415, * S986
  • VIM P08670 Vimentin * S39, * S56, * Y61,
  • PIK3 class I as well as Aktl are components of the Mas receptor signaling pathway and involved in eNOS activation. In addition, these kinases are also components of the insulin / growth factor signaling pathway. However, a PIK3 isoform that belongs to class II and is not an upstream component of the Aktl signaling pathway has been identified in the present invention.
  • the cellular effects of PIK3C2A have not yet been fully elucidated, but it has been reported that PIK3C2A induces translocation of GLUT4 to the plasma membrane in response to insulin stimulation. (Sampaio WO et al., 2007.
  • Akt1 S124 leads to its activation. However, it is only after T308 and S473 phosphorylation of this kinase that its activation is complete, allowing its translocation to the nucleus, where it phosphorylates FOX01 at T24, S256 and S319, and inactivates this transcription factor, which leads to cell proliferation. Sert4 phosphorylation of Akt1 may contribute to Akt protein response to subsequent activation events. Since Sampaio et al. (2007) have shown that Ang- (1-7) can stimulate Akt activation through Ser473 phosphorylation, Akt1 Ser124 phosphorylation in Ang- (1-7) -treated cells probably stimulates activation.
  • Akt1 by facilitating its full activation by phosphorylation of Thr308 and Ser473, thereby stimulating endothelial functions.
  • the present invention suggests the concomitant use of PI3K / Akt pathway inhibitors, which would silence the activation of Akt1 by Ang- ( 1-7), thereby increasing inhibition of tumor growth (Ackah E et al., 2005.
  • Akt1 / protein kinase Balpha is critical for ischemic and VEGF-mediated angiogenesis. J Clin Invest.
  • Ang- (1-7) may inhibit tumor growth by activating FoxO1, a transcription factor involved, among other mechanisms, in tumor suppression and inhibition of angiogenesis.
  • PI3K / Akt signaling pathway regulates transcription factor FoxOI, through Ser256, Ser319 and Thr24 Akt phosphorylation, inducing FoxOI translocation to the cytoplasm, which leads to inhibition of FoxOI-dependent transcription and allows cell proliferation.
  • Ang- (1-7) treatment stimulates FoxOI Ser256 dephosphorylation, probably activating it.
  • FoxOI dephosphorylation in Ang- (1-7) -stimulated cells contrasts with the activation of the PI3K pathway by angiostensin- (1-7), which would lead to FoxOI phosphorylation.
  • Ang- (1-7) activates FoxOI via a path independent of the PI3K / Akt pathway.
  • the present invention demonstrates that it would be interesting to stimulate Ang- (1-7) cells for FoxOI activation and its anticancer properties, but simultaneously inhibit the PI3K / Akt pathway, potentiating inhibition of tumor progression.
  • Akt Akt's key functions.
  • One of the major downstream effector proteins of this pathway is the 1 mTOR complex.
  • the 40 kDa proline rich Akt substrate PRAS40 or Akt1S1 is an mTOR binding partner which inhibits mTOR activity through its binding.
  • Akt phosphorylates Akt1S1 at Thr246, resulting in Akt1S1 dissociation from mTORCI and binding of Akt1S1 to 14-3-3 protein.
  • Ang- (1-7) treated cells show an increase in Ak24 S1 Thr246 dephosphorylation compared to control cells. This result indicates that Ang- (1-7) induces PRAS40 dephosphorylation which will stimulate its binding to mTOR and consequently inhibit it.
  • Ang- (1-7) is implicated in inhibiting cell growth by blocking mTOR activity (Wullschleger S, Loewith R, Hall MN, 2006. TOR signaling in growth and metabolism. Celi. Feb 10; 124 ( 3): 471-84 Review PubMed PMID: 16469695; Vander Haar E et al., 2007. Insulin signalling to mTOR mediated by the Akt / PKB substrate PRAS40 Nat Celi Biol. Mar; 9 (3): 316-23 Epub 2007 Feb 4. PubMed PMID: 17277771).
  • Ang- (1-7) can also inhibit tumor growth by regulating MAP protein kinases.
  • Phosphoproteome of Ang- (1-7) -stimulated endothelial cells revealed that MAPK1-Y dephosphorylation occurs in treated cells.
  • MAPK1 dephosphorylation also demonstrated by Sampaio (2007), induces MAPK1 inactivation, since this phosphosite regulates the activity of this kinase. (Sampaio WO, 2007.
  • Angiotensin- (1-7) counterregulates angiotensin II signaling in human endothelial cells. Hypertension. 2007 Dec; 50 (6): 1093-8. Epub 2007 Nov 5.
  • HDAC1 is a nuclear enzyme that deacetylates Plant residues in the N-terminal part of histones H2A, H2B, H3 and H4, inducing cell proliferation and reducing gene expression.
  • the phosphorylation of HDAC1 serine 421 and 423 promotes its activation.
  • Ang- (1-7) treatment induces rapid dephosphorylation of these sites, which probably decreases HDAC1 activity ( Figure 1 and Table II).
  • Ang- (1-7) Treatment of endothelial cells with Ang- (1-7) induces phosphorylation of PI3K-C2a Ser338, Rasip 1 Ser326 phosphorylation and DYRK1 B Tyr273 phosphorylation. These proteins modulate processes in which Ang- (1- 7) is also involved. PI3K-C2a and DYRK1 B are involved in cell survival, while Rasip 1 is an essential protein for blood vessel morphogenesis.
  • Mirk / Dyrk1 B a multifunctional dual-specificity kinase involved in growth arrest, differentiation, and cell survival Cell Biochem Biophys 45 (3) : 303-15 Review PubMed PMID: 16845176 Xu K et al 2009. Rasip 1 is required for endothelial cell motility, angiogenesis and vessel formation Dev Biol May 15; 329 (2): 269-79 Epub 2009 Mar 6. PubMed PMID: 19272373; PubMed Central PMCID: PMC2683470; Xu K et al., 2011. Blood vessel tubulogenesis requires Rasipl regulation of GTPase sign Aling Dev Cell. Apr 19,20 (4): 526-39. Epub 2011 Mar 10.
  • Angiotensin- (1-7) inhibits growth of human lung adenocarcinoma xenografts in nude mice through reduction in cyclooxygenase-2. Cancer Res. 2007 Mar 15; 67 (6): 2809-15. PubMed PMID: 17363603.).
  • Ang- (1-7) in endothelial cells also affects the phosphorylation state of other proteins not mentioned previously, probably altering the execution of their activities. Proteins involved in the mechanisms of tumor suppression, cell growth, metabolism, apoptosis and others.
  • Proteins showing increased phosphorylation of certain residues include: ADAM9 (pS758 / pT761), AHNAK (pS559), AKAP12 (pS697 / 698), AKAP2 (pS135), Akt1 (pS124), ANP32B (pT244) ), BAG3 (pS264), CANX (pS583), CFL1 (pS3), CYBRD1 (pT285), DYRK1B (pY273), ERC1 (pS37), ESAM (pS1459), FLNA (pS1459), FRMD4A (pS711), HIST1 HIST1 H1C (pS173), HIST1 H1 E (pS187), HNRNPC (pS233), HSPB1 (pS82), LARP1 (pT782 / 788), LMNA (pS390), LMNA (pS406 / 407),
  • Ang- (1-7) treatment in endothelial cells also induced an increase in dephosphorylation of certain residues (marked in parentheses) of some proteins, which include: AHNAK (pS5448), AHSG (pS135) CTNND1 ( pS349 / 352), AHSG (pS138), AKAP12 (pS1328), AKAP12 (pS696 / 697/698), Akt1S1 (pT246), ARPP19 (pS62), CALD1 (pS789), CAV1 (pS37), CTNND1 (pS252I), DY2 (pS194), EIF5B (pS214), FAM129B (pS679 / 683), FMNL2 (pS171), FOX01 (pS256), HDAC1 (pS421 / 423), HIST1 H1E (pT4), HNRNPA3 (pY360), HNRNPH) (pS414)
  • Example 6 Survival of tumor cells subjected to treatment with the combination of Angiotensin 1-7 (10 ⁇ 6 ) and PI3K inhibitors (wortmannin and LY294002).
  • Human alveolar adenocarcinoma (A549) and human prostate cancer (Du145) cell lines were grown in DMEM-F12 medium supplemented with fetal bovine serum and penicillin and streptomycin antibiotics, and incubated at 37 ° C and 5% CO 2 . After cell counting using cytometric chamber, the strains were diluted to a concentration of 2 x 10 4 cells.ml -1 in DMEM-F12 medium containing serum. 250 ⁇ of this preparation was distributed into each well of the 96-well plate (Nunclon), except for half of the last row, where only 250 ⁇ of medium was added.
  • A549 cells were treated with wortmannin alone or in combination with angiotensin 1-7 (10 " 6 ), while Du145 cells were treated with LY294002 alone. or in combination with angiotensin 1-7 (10 "6 ).
  • 125 ⁇ DMEM-F12 was added in the absence or presence of angiotensin 1-7 (10 "6 ).
  • 125 ⁇ Wortmannin was added (250 ⁇ ) to A549 and 125 cells.
  • LY294002 were added (1000 ⁇ ) to Du145 cells Serial dilutions were made: 125 ⁇ of the first column were mixed with the next column Then 125 ⁇ of the second column were added to the third column and homogenized, and so on After two days of treatment, these cells were incubated for 3 hours in the presence of 25 ⁇ Alamar blue (Invitrogen) After this period, the plate was read by a spectrometer using a 570 nm excitation and 585 nm emission filter.
  • PI3K inhibitors such as wortmannin and LY294002 at certain doses increases the efficacy of these drugs in inhibiting tumor cell growth.
  • Human alveolar adenocarcinoma cell lines (A549) were grown in DMEM-F12 medium supplemented with fetal bovine serum and penicillin and streptomycin antibiotics, and incubated at 37 ° C and 5% CO 2 . These cells were incubated with DMEM-F12 alone, without serum or in the presence of angiotensin 1-7 (10 "7 ) for 10 min. Localization of FoxOI in A549 strain cells was performed by immunolocation with anti-FoxOl antibody.
  • the coverslips were slide-bladed and sealed with VectaShield containing DAPI.
  • the images were captured using a confocal microscope equipped with a DXM 1200 F camera. The images were analyzed using the Image J program.
  • A549 cells after treatment with angiotensin 1-7, had a higher fluorescence intensity of FoxOI in the nucleus compared to these untreated cells. This result indicates that a higher FoxOI localization occurs in the nucleus of Ang- (1-7) treated cells.
  • Ang- (1-7) treatment probably causes FoxOI dephosphorylation in A549 cells, as shown for HAEC cells in example 5, which leads to migration of this protein to the nucleus of tumor cells, where it will inhibit the transcription of genes involved in cell growth and proliferation and activation of apoptotic genes. Therefore, angiotensin 1-7 by inducing FoxOI location change can inhibit tumor growth (Figure 3).

Abstract

La présente invention concerne des compositions pharmaceutiques contenant une combinaison d'Ang-(1-7) ou d'un autre agoniste du récepteur Mas avec des inhibiteurs PI3K/Akt, pour le traitement thérapeutique anticancer. La combinaison d'Ang-(1-7) et d'inhibiteurs de PI3K/Akt provoque l'inhibition de la progression du cancer par inhibition de la croissance ou de la prolifération cellulaire, ou l'activation de la mort cellulaire par apoptose chez des mammifères, et notamment chez l'être humain.
PCT/BR2012/000556 2011-12-29 2012-12-27 Compositions pharmaceutiques contenant de l'ang-(1-7) ou un autre agoniste du récepteur mas avec inhibiteurs de pi3k/akt pour le traitement thérapeutique anticancer WO2013097017A1 (fr)

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