Biomedical subjects

Maria Vilenchik

Publications and source records attributed to Maria Vilenchik.

4 recordsLinked to original sources

PubMed2004

Hsp90: the vulnerable chaperone.

The molecular chaperone Hsp90 has emerged as an important target in cancer treatment because of its roles in maintaining transformation and regulating the function of proteins involved in apoptotic, survival and growth pathways. Many Hsp90 inhibitors function by binding to the N-terminal ATP pocket, but the chaperone has many other vulnerable points. Agents that interact with its C-terminus or modify its post-translational status represent additional ways of interfering with chaperone activity. This review will discuss several emerging classes of Hsp90 inhibitors and their modes of action.

Animals↗

PubMed2004

Targeting wide-range oncogenic transformation via PU24FCl, a specific inhibitor of tumor Hsp90.

Agents that inhibit Hsp90 function hold significant promise in cancer therapy. Here we present PU24FCl, a representative of the first class of designed Hsp90 inhibitors. By specifically and potently inhibiting tumor Hsp90, PU24FCl exhibits wide-ranging anti-cancer activities that occur at similar doses in all tested tumor types. Normal cells are 10- to 50-fold more resistant to these effects. Its Hsp90 inhibition results in multiple anti-tumor-specific effects, such as degradation of Hsp90-client proteins involved in cell growth, survival, and specific transformation, inhibition of cancer cell growth, delay of cell cycle progression, induction of morphological and functional changes, and apoptosis. In concordance with its higher affinity for tumor Hsp90, in vivo PU24FCl accumulates in tumors while being rapidly cleared from normal tissue. Concentrations achieved in vivo in tumors lead to single-agent anti-tumor activity at non-toxic doses.

Adenine↗

PubMed2003

Microtiter cell-based assay for detection of agents that alter cellular levels of Her2 and EGFR.

Overexpression of the transmembrane tyrosine kinases Her2 and EGFR is associated with aggressive malignancies, and several therapeutic strategies targeting the two receptors are now in various stages of clinical development. Most of the known agents block the activation or inhibit the activity of the kinases; however, a more significant therapeutic outcome may result from degrading these oncoproteins. Here, we report the development of a microtiter cell-based assay that sensitively detects cellular levels of Her2 and EGFR. The assay is useful in identifying small molecules that alter cellular levels of these kinases and in quantifying their effect. The method gives results comparable to Western blot, but it is faster, less labor intensive, and amenable to high throughput.

Actins↗

PubMed2002

Antisense RNA down-regulation of bcl-xL Expression in prostate cancer cells leads to diminished rates of cellular proliferation and resistance to cytotoxic chemotherapeutic agents.

bcl-xL is a M(r) 26,000 bcl-2 homologue that is highly expressed in prostate cancer cells. In previous studies, the down-regulation of its expression by antisense oligonucleotides led to resistance. In this work, the 445-bp 5' terminus of the bcl-xL cDNA was cloned in the antisense orientation and stably transfected into DU145 and LNCaP prostate cancer cells. In the DU145 (and to a lesser extent the LNCaP) transfectants, phenotypic changes (versus mock-transfected cells) included an increase in doubling time (from 36 to 175 h) in the clone in which bcl-xL protein expression was 25% of control. The transfectants did not demonstrate characteristic apoptotic changes, as demonstrated by 4',6-diamidino-2-phenylindole staining, lack of either DNA laddering, caspase-3 activation, or poly(ADP)ribose and lamin cleavage, and the absence of a significant sub-G(0) population. Cell cycle analysis demonstrated an increase in a tetraploid population (from 28% to 66%), as well as the appearance of a hypertetraploid population. Levels of cIAP-1 protein were almost undetectable in the mock cells but increased at least 25-fold in the DU145 transfectants. The down-regulation of bcl-xL in both DU145 (and to a much lesser extent in LNCaP) cells led to their resistance to cytotoxic agents, including docetaxel, mitoxantrone, etoposide, vinblastine, and carboplatin. Reversion of bcl-xL expression in stable DU145 transfectants to nearly the levels found in the mock-transfected cells was accomplished by retroviral infection of the cells with a bcl-xL sense cDNA under control of a prolific promoter. This led to a dramatic increase in the growth rate and in BrdUrd incorporation, as well as a sharp decrease in the expression of cIAP-1 protein. Overall, these findings highlight the adaptability of prostate cancer cells to loss of bcl-xL and suggest that in addition to its prosurvival role, bcl-xL protein may also be involved in the regulation of the rate of cellular proliferation.

Antineoplastic Agents↗