Abnormal activation of phosphatidylinositol-3-kinase (PI3K) happens to be validated since an important action within the trigger and additionally maintenance of human tumors. Akt is a serine-threonine kinase turned on by growth factors or alternatively survival factors throughout PI3K to promote mobile growth and also survival . Constituent pathway activation might result from using specific and/or complementary biological events such as (a) constitutively activating mutations or amplification of receptor tyrosine kinases (RTK); (b) amplification of PI3K; (c) activating mutations in the PIK3CA gene encoding the p110α catalytic subunit; (d) overexpression of the downriver kinase Akt; (e) reduction or perhaps inactivating mutations of the tumor suppressor cistron phosphatase and additionally tensin homolog (PTEN), some kind of endogenous bad regulator of the PI3K pathway; or alternatively ( f ) constituent recruitment and activation by mutant types of the RAS oncogene . One significant function of turned on PI3K in cells is the inhibition of apoptosis, as well as Akt is a superb candidate for mediating all PI3K-dependent cellular survival responses. Akt happens to be a antiapoptotic factor in lot of different cellular death stimuli, as an example the withdrawal of extracellular signal factors, oxidative and also osmotic fret, irradiation and treatment along with chemotherapeutic medication, and additionally ischaemic shock. Undoubtedly, Akt activation and overexpression is usually connected along with resistance to chemotherapy or radiotherapy. Reversal of drug resistance has become shown with PI3K inhibitors and PTEN overexpression in PTEN-null tissues. Dominant-negative mutants of Akt enhance the cytotoxicity of chemotherapeutic agents, suggesting {a particular of Akt in drug resistance. Thus, scientifically appropriate small-molecule inhibitors of Akt have great potential in cancer medication. Moreover, the identification of suitable classes of chemotherapeutic agents which can be sensitive by Akt inhibition is definitely desirable to guide the clinical application of Akt inhibitors.
MK-2206 is an orally active allosteric Akt chemical which is below development for the treatment of sturdy tumors. MK-2206 is a very potent and selective Akt chemical. It is equally potent towards purified recombinant human Akt1 (IC50, 5 nmol/L) and additionally Akt2 enzyme (IC50, 12 nmol/L) as well as around 5-fold less potent against human Akt3 (IC50, sixty-five nmol/L). Within the present report, we describe the fusion negative effects of MK-2206 with numerous anticancer drugs, most notably docetaxel, carboplatin, gemcitabine, 5-fluorouracil (5-FU), doxorubicin, camptothecin, as well as RTK inhibitors for example lapatinib and also erlotinib.
MK-2206 is an orally active allosteric Akt chemical which is below development for the treatment of sturdy tumors. MK-2206 is a very potent and selective Akt chemical. It is equally potent towards purified recombinant human Akt1 (IC50, 5 nmol/L) and additionally Akt2 enzyme (IC50, 12 nmol/L) as well as around 5-fold less potent against human Akt3 (IC50, sixty-five nmol/L). Within the present report, we describe the fusion negative effects of MK-2206 with numerous anticancer drugs, most notably docetaxel, carboplatin, gemcitabine, 5-fluorouracil (5-FU), doxorubicin, camptothecin, as well as RTK inhibitors for example lapatinib and also erlotinib.
1. Bellacosa A, Testa JR, Staal SP, Tsichlis
PN. A retroviral oncogene, akt, encoding a serine-threonine kinase containing
an SH2-like region. Science 1991;254:274–7.
2. Burgering BM, Coffer PJ. Protein kinase B
(c-Akt) in phosphatidylinositol- 3-OH kinase signal transduction. Nature
1995;376:599–602.
3. Datta SR, Brunet A, Greenberg ME. Cellular
survival: a play in three Akts. Genes Dev 1999;13:2905–27.
4. Carnero A, Blanco-Aparicio C, Renner O,
Link W, Leal JFM. The PTEN/PI3K/AKT signaling pathway in cancer, therapeutic
implications. Curr Cancer Drug Targets 2008;8:187–98.
5. Tokunaga E, Oki E, Egashira A, et al.
Deregulation of the Akt pathway in human cancer. Curr Cancer Drug Targets
2008;8:27–36.
6. Maira S-M, Voliva C, Garcia-Echeverria C.
Class IA PI3 kinase: from their biological implication in human cancers to drug
discovery. Expert Opin Ther Targets 2008;12:223–38.
7. Vivanco I, Sawyers CL. The
phosphatidylinositol 3-kinase AKT pathway in human cancer. Nat Rev Cancer
2002;2:489–501.
8. Nogueira V, Park Y, Chen CC, et al. Akt
determines replicative senescence and oxidative or oncogenic premature
senescence and sensitizes cells to oxidative apoptosis. Cancer Cell 2008;14:427–9.
9. Pastukh V, Ricci C, Solodushko V, Mozaffari
M, Schaffer SW. Contribution of the PI 3-kinase/Akt survival pathway toward
osmotic preconditioning. Mol Cell Biochem 2005;269:59–67.
10. Mullonkal CJ, Toledo-Pereyra LH. Akt in
ischemia and reperfusion. J Invest Surg 2007;20:195–203.
11. West KA, Castillo SS, Dennis PA. Activation
of the PI3K/Akt pathway and chemotherapeutic resistance. Drug Resist Updat
2002;5: 234–48.
12. Winograd-Katz SE, Levitzki A. Cisplatin
induces PKB/Akt activation and p38 MAPK phosphorylation of the EGF receptor.
Oncogene 2006;25:7381–90.
13. Liu LZ, Zhou XD, Qian G, Shi X, Fang J,
Jiang BH. AKT1 amplification regulates cisplatin resistance in human lung
cancer cells through the mammalian target of rapamycin/p70S6K1 pathway. Cancer
Res 2007;67:6325–32.
14. Bellacosa A, Kumar CC, Di Cristofano A,
Testa JR. Activation of AKT kinases in cancer: implications for therapeutic
targeting. Adv Cancer Res 2005;94:29–86.
15. Yan X, Fraser M, Qiu Q, Tsang Benjamin K.
Over-expression of PTEN sensitizes human ovarian cancer cells to
cisplatin-induced apoptosis in a p53-dependent manner. Gynecol Oncol
2006;102:348–55.
16. Clark AS, West K, Streicher S, Dennis PA.
Constitutive and inducible Akt activity promotes resistance to chemotherapy,
trastuzumab, or tamoxifen in breast cancer cells. Mol Cancer Ther 2002;1:707–17.
17. She QB, Solit DB, Ye Q, O'Reilly KE, Lobo
J, Rosen N. The BAD protein integrates survival signaling by EGFR/MAPK and
PI3K/Akt kinase pathways in PTEN-deficient tumor cells. Cancer Cell 2005;8:287–97.
18. Brognard J, Clark AS, Ni Y, Dennis PA.
Akt/protein kinase B is constitutively active in non-small cell lung cancer
cells and promotes cellular survival and resistance to chemotherapy and
radiation. Cancer Res 2001;61:3986–97.
19. Dillon RL, White DE, Muller WJ. The
phosphatidyl inositol 3-kinase signaling network: implications for human breast
cancer. Oncogene 2007;26:1338–45.
20. Jiang BH, Liu LZ. PI3K/PTEN signaling in
tumorigenesis and angiogenesis. Biochim Biophys Acta 2008;1784:150–8.
21. Lindsley CW, Zhao Z, Leister WH, et al.
Allosteric Akt (PKB) inhibitors: discovery and SAR of isozyme selective
inhibitors. Bioorg Med Chem Lett 2005;15:761–4.
22. Barnett SF, Defeo-Jones D, Fu S, et al.
Identification and characterization of pleckstrin-homology-domain-dependent and
isoenzymespecific Akt inhibitors. Biochem J 2005;385:399–408.
No comments:
Post a Comment