Levels of p27kip1 determine Aplidin sensitivity

Moneo, Victoria; Serelde, Beatriz G.; Leal, Juan F.M.; Blanco‐Aparicio, Carmen; Dı́az-Uriarte, Ramón; Aracil, Miguel; Tercero, Juan Carlos; Jimeno, J.; Carnero, Amancio

doi:10.1158/1535-7163.mct-06-0729

Cited by 31 publications

(33 citation statements)

References 26 publications

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“…34 One day before transfection, 2 Â 10 4 MEL HO human melanoma cells per well were seeded in 6-well plates containing 2 ml of normal growth medium. Total cell number was determined the day before the transfection.…”

Section: Small Interfering Rna Gene Silencing Methodsmentioning

confidence: 99%

The NK-1 receptor is expressed in human melanoma and is involved in the antitumor action of the NK-1 receptor antagonist aprepitant on melanoma cell lines

Muñoz

Rosso

Robles‐Frías

et al. 2010

Laboratory Investigation

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Melanoma, the most deadly form of skin cancer, is aggressive and resistant to current therapies. It has been previously reported that the substance P and neurokinin-1 (NK-1) receptor antagonists induce cell proliferation and cell inhibition, respectively, in human melanoma cell lines. Aprepitant is a selective high-affinity antagonist of the human NK-1 receptor. Until now, this drug has been used as an anxiolytic, antidepressant and antiemetic. Moreover, the antitumor action of aprepitant has been previously reported. However, the presence of NK-1 receptors in human melanomas and whether the antitumor action of the NK-1 receptor antagonist aprepitant is exerted on human malignant melanomas have not been previously described. The aims of this study are to show the presence of NK-1 receptors in human malignant melanomas and the antitumoral action of aprepitant against several human melanoma cell lines. Immunoblot analysis was used to determine the presence of NK-1 receptors in human melanoma cell lines, and immunohistochemistry was used to demonstrate NK-1 receptors in human melanoma samples. We performed an in vitro study of the cytotoxicity of the NK-1 receptor antagonist aprepitant on human melanoma cell lines. A coulter counter was used to determine viable cell numbers, followed by application of the tetrazolium compound MTS. The DAPI method was applied to demonstrate apoptosis. We observed that NK-1 receptors were present in all the melanoma samples studied as well as in human melanoma cell lines. We also showed that melanoma cell lines expressed mRNA for the NK-1 receptor. Moreover, after using a knockdown method, we showed that NK-1 receptors are involved in the viability of tumor cells. In this study, we also report that aprepitant, at 10-60 mM concentrations, elicits cell growth inhibition in a concentration-dependent manner in all melanoma cell lines studied, that the specific antitumor action of aprepitant occurs through the NK-1 receptor and that melanoma cell death is due to apoptosis. These findings show for the first time that the NK-1 receptor may be a promising new target and that the NK-1 receptor antagonist aprepitant could be a candidate as a new antitumor drug in the treatment of human melanoma.

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Section: Small Interfering Rna Gene Silencing Methodsmentioning

confidence: 99%

The NK-1 receptor is expressed in human melanoma and is involved in the antitumor action of the NK-1 receptor antagonist aprepitant on melanoma cell lines

Muñoz

Rosso

Robles‐Frías

et al. 2010

Laboratory Investigation

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“…We carried out this method according to the manufacturer's instructions (Invitrogen, Madrid, Spain) and according to a previous study [34]. One day before transfection, 2×10 4 cells per well from the BE-13 and SD-1 human leukemia cell lines were seeded in 6-wells plates containing 2 ml of normal growth medium.…”

Section: Small Interfering Rna (Sirna) Gene-silencing Methodsmentioning

confidence: 99%

The NK-1 receptor is expressed in human leukemia and is involved in the antitumor action of aprepitant and other NK-1 receptor antagonists on acute lymphoblastic leukemia cell lines

Muñoz¹,

González-Ortega²,

Coveñas³

2010

Invest New Drugs

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Substance P and neurokinin-1 (NK-1) receptor antagonists respectively induce cell proliferation and cell inhibition in human cancer cell lines. In acute lymphoblastic leukemia (ALL), substance P is expressed in human blast cells. However, the possible presence of NK-1 receptors in human ALL and the issue of whether the antitumor action of NK-1 receptor antagonists is exerted or not on human ALL (T-ALL BE-13 and B-ALL SD-1 cell lines) remain unknown. An immunoblot analysis was performed and an in vitro study of the cytotoxicity of three NK-1 receptor antagonists (L-733,060, L-732,138, aprepitant) was carried out on both cell lines. NK-1 receptors were found in those cell lines, and both expressed mRNA for this receptor. Using a knockdown method, we demonstrate that NK-1 receptors are involved in the viability of tumor cells. TAC1R cDNA was detected in the ALL cell lines by real-time quantitative RT-PCR. We also observed that the three NK-1 receptor antagonists elicited the inhibition of ALL cell growth; that the specific antitumor action of the NK-1 receptor antagonists occurs through the NK-1 receptor, and that ALL cell death is due to apoptosis. These findings suggest that NK-1 receptor antagonists could be considered as new antitumor drugs for the treatment of human ALL.

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“…Moneo and colleagues reported that the levels of p27 sensitize sarcoma cell lines to Aplidin, a macrocyclin depsipeptide showing antitumor activity in various human tumors (25). Higher p27 levels were recently found to be associated with improved response of breast cancer cell lines to 2 rapalogs, temsirolimus and everolimus (RAD001; ref.…”

Section: Introductionmentioning

confidence: 99%

Levels of p27 Sensitize to Dual PI3K/mTOR Inhibition

Lee

Theodoropoulou

Graw

et al. 2011

Molecular Cancer Therapeutics

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Constitutive activation of the phosphatidylinositol 3-kinase (PI3K)/AKT/mTOR signaling cascade occurs in a variety of human malignancies, where it sustains tumor cell proliferation and survival. Pharmacologic blockade of this pathway exerts antineoplastic activity by triggering apoptosis and/or cell-cycle arrest. Pituitary adenomas show activation of the PI3K/AKT/mTOR pathway, but only a fraction of them respond in vitro to the antiproliferative action of rapamycin and RAD001 (mTOR inhibitors), possibly because of the described negative feedback loop on AKT which reactivates the signaling cascade. Rats affected by the multiple endocrine neoplasia-like syndrome (MENX) develop pituitary adenomas showing increased activated AKT. In this study, we comparatively investigated the antitumor potential of the novel dual PI3K/mTOR inhibitor NVP-BEZ235 and the single mTOR inhibitor RAD001 on rat pituitary adenoma cells in primary culture. NVP-BEZ235 inhibits the PI3K pathway both upstream and downstream of AKT, thereby preventing the negative feedback loop. NVP-BEZ235 was more effective than RAD001 in reducing cell viability of pituitary adenomas. Consistently, NVP-BEZ235 treatment decreased Akt and S6 phosphorylation and triggered apoptosis. Because MENX is caused by a germline loss-of-function mutation in the cell-cycle inhibitor p27Kip1, we investigated the relationship between this defect and response to NVP-BEZ235 treatment. The levels of p27Kip1 positively correlate with the response to NVP-BEZ235 treatment. Combined treatment with NVP-BEZ235 and the proteasome inhibitor bortezomib, which increases p27Kip1 amount, shows synergistic antiproliferative effects on pituitary adenoma cells. Our data suggest that NVP-BEZ235 may represent an effective therapeutic modality for pituitary adenomas and that p27Kip1 levels represent a potential predictor of response to dual PI3K/mTOR inhibition.

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Levels of p27kip1 determine Aplidin sensitivity

Cited by 31 publications

References 26 publications

The NK-1 receptor is expressed in human melanoma and is involved in the antitumor action of the NK-1 receptor antagonist aprepitant on melanoma cell lines

The NK-1 receptor is expressed in human melanoma and is involved in the antitumor action of the NK-1 receptor antagonist aprepitant on melanoma cell lines

The NK-1 receptor is expressed in human leukemia and is involved in the antitumor action of aprepitant and other NK-1 receptor antagonists on acute lymphoblastic leukemia cell lines

Levels of p27 Sensitize to Dual PI3K/mTOR Inhibition

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