<b>
                     <i>In vitro</i>
                  </b> Combination Treatment with Perifosine and UCN-01 Demonstrates Synergism against Prostate (PC-3) and Lung (A549) Epithelial Adenocarcinoma Cell Lines

Dasmahapatra, Girija; Didolkar, Parijat; Alley, Michael C.; Ghosh, Somiranjan; Sausville, Edward A.; Roy, Krishnendu

doi:10.1158/1078-0432.ccr-03-0534

Cited by 62 publications

(36 citation statements)

References 34 publications

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“…Furthermore, the ability of enforced activation of Akt to protect cells from this drug combination supports the notion that disruption of Akt signaling plays a functional role in the observed lethality. It should be noted that diminished expression of total and phosphorylated Akt was attenuated by caspase inhibition, consistent with evidence that signaling proteins in general, 39,40 and Akt in particular, 41 are subject to caspase-dependent degradation. Alternatively, inactivation of Akt, as well as other signaling proteins (eg Bcr/Abl, Raf/MEK/ERK) may reflect acetylation of chaperones such as Hsp90, leading to misfolding and degradation of client proteins.…”

Section: Discussionsupporting

confidence: 79%

Synergistic interactions between MEK1/2 and histone deacetylase inhibitors in BCR/ABL+ human leukemia cells

Dasmahapatra

Dent

et al. 2005

Leukemia

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Interactions between the histone deacetylase inhibitor SAHA and the pharmacologic MEK1/2 inhibitor PD184352 were examined in Bcr/Abl þ human leukemia cells. Coadministration of minimally toxic concentrations of SAHA (or sodium butyrate) and PD184352 (or U0126) resulted in a synergistic increase in mitochondrial damage, caspase activation, and apoptosis in K562 and LAMA 84 cells. Similar interactions were observed in CD34 þ cells from two patients with CML and in imatinib mesylate-resistant K562 cells but not in normal human CD34 þ bone marrow cells. These events were associated with a marked increase in ROS generation, inactivation of ERK and Akt, downregulation of p21 CIP1 , Bcr/Abl, and cyclin D 1 , and activation of JNK. Of these events, ROS generation, ERK inactivation, and cytochrome c/AIF release were largely caspase-independent, whereas the other phenomena displayed varying degrees of caspase-dependence. Using pharmacologic and genetic approaches, generation of ROS, p21 CIP1 downregulation, and inactivation of Akt and MEK were found to play significant functional roles in SAHA/PD184352-mediated lethality, whereas JNK activation and Raf-1 downregulation were determined to represent secondary events. These findings indicate that interruption of the MEK/ERK pathway substantially lowers the threshold for HDAC inhibitor-mediated oxidative injury, mitochondrial dysfunction, and apoptosis, suggesting that this approach warrants further examination in Bcr/Abl þ -related malignancies.

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Section: Discussionsupporting

confidence: 79%

Synergistic interactions between MEK1/2 and histone deacetylase inhibitors in BCR/ABL+ human leukemia cells

Dasmahapatra

Dent

et al. 2005

Leukemia

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“…In A549, Calu1 and H596 NSCLC cell lines the staurosporine analog and Chk-1 inhibitor UCN-01 potentiate cisplatininduced apoptosis, which is correlated with abrogation of the S and G2 checkpoints. 37 UCN-01 can also sensitize A549 NSCLC cells to perifosine, which is correlated with a decrease in Akt phosphorylation and increase in PARP cleavage, 38 supporting Akt involvement in cell death. However, UCN-01 inhibits purified Chk-1 from phosphorylation of a Cdc25C motif, 39 making it difficult to understand if the death of NSCLC cells is dependent on Akt or direct Chk-1 inhibition.…”

Section: Discussionmentioning

confidence: 88%

Inhibitors of the PI3‐kinase/Akt pathway induce mitotic catastrophe in non‐small cell lung cancer cells

Hemström

Sandström

Zhivotovsky

2006

Intl Journal of Cancer

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Non-small cell lung cancer cells (NSCLC) are more resistant to anticancer treatment as compared with other types of cancer cells. Recently (Hemstr€ om et al., Exp Cell Res 2005;305:200-13) we showed that apoptosis of U1810 NSCLC cells induced by the staurosporine analog PKC 412 correlated with inhibition of Akt and ERK1/2, suggesting the involvement of these kinases in cell survival. Here we investigated the contribution of the PI3-kinase/Akt and MEK/ERK pathways to survival of NSCLC cells. The two signaling pathways were studied by using different combinations of the PI3-kinase inhibitors LY-294002 and wortmannin, the Akt activator Ro 31-8220, the MEK inhibitor PD 98059 and PKC 412. PI3-kinase inhibitors induced apoptosis-like death in U1810 cells. H157 cells in general were relatively resistant to PI3 kinase/Akt inhibitors yet these compounds sensitized cells to the DNA-damaging drug VP-16, while Ro 31-8220 could not. PD 98059 only had a sensitizing effect on H157 cells when combined with PI3-kinase inhibition and VP-16. Key words: mitotic catastrophe; non-small cell lung carcinoma; PI3-kinase; Akt; apoptosis Cell lines derived from non-small cell lung carcinoma (NSCLC) are most often characterized by cellular resistance towards anticancer drugs and radiation. 1 Efficiency of action of DNA-damaging drugs used in anticancer therapy depends on the successful ability to induce growth arrest and to activate the cell death machinery. 2 Apoptosis induced by DNA damage is typically associated with activation of a family of proteases, the caspases, as a result of a sequence of mitochondria-mediated events. The caspases cleave many proteins, eventually leading to biochemical and morphological apoptosis-specific changes. In addition to activation of the caspases, mediated by release of cytochrome c, several proteins, such as apoptosis inducing factor (AIF) and endonuclease G are also released from mitochondria, translocate to the nuclei and induce chromatin condensation and cell death independently of caspases.Cell cycle regulation is also an important determinant for efficiency of cell death in response to DNA damage. For example, topoisomerase inhibitors are suggested to be particularly effective in S-phase when DNA replication occurs, 3 while irradiated cells are most sensitive at G2/M phase. 4 DNA-damaged cells are removed by cell death following activation of the DNA damage checkpoints in G1 and G2-phases of the cell cycle. 5 There are many mechanisms for cells being resistant to DNA damage. 6 For example, resistant lung cancer cells have an increased activity of DNAdependent protein kinase (DNA-PK) and DNA repair, correlating with a decreased incidence of cell death, suggesting involvement of DNA-PK in tumor survival. 7,8 Aberrant signaling of other kinases, such as the Ras/MEK/ERK and PI3-kinase/Akt pathways is also contributes to cell death resistance. In NSCLC-patients phospho-Akt overexpression confers a stage-independent survival disadvantage 9 and in NSCLC cell lines a high activity of Akt promotes cellular...

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“…Perifosine has marked cytotoxic effects on human tumor cell lines, in particular larynx carcinoma, breast cancer, small cell lung cancer, prostate cancer and colon carcinoma. Of special interest is the synergistic antiproliferative effect observed when perifosine was used in combination with UCN-01 in cell culture assays with PC3 and A459 tumor cells (Dasmahapatra et al, 2004), with the antiepidermal growth factor receptor antibody, cetuximab, in PTENdeficient cancer cells (Li et al, 2006) and with the hsp90 inhibitor 17-DMAG (see next section) in multiple myeloma cells (Huston et al, 2008). Blocking simultaneously distinct components of the PI3K/Akt pathway seems to enhance the inhibition of phosphorylation of Akt along with activation of the apoptotic pathway.…”

Section: Phospholipids-antagonists Of Ph Domainsmentioning

confidence: 99%

Drug discovery approaches targeting the PI3K/Akt pathway in cancer

2008

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In vitro Combination Treatment with Perifosine and UCN-01 Demonstrates Synergism against Prostate (PC-3) and Lung (A549) Epithelial Adenocarcinoma Cell Lines

Cited by 62 publications

References 34 publications

Synergistic interactions between MEK1/2 and histone deacetylase inhibitors in BCR/ABL+ human leukemia cells

Synergistic interactions between MEK1/2 and histone deacetylase inhibitors in BCR/ABL+ human leukemia cells

Inhibitors of the PI3‐kinase/Akt pathway induce mitotic catastrophe in non‐small cell lung cancer cells

Drug discovery approaches targeting the PI3K/Akt pathway in cancer

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