Inhibition of phosphatidylinositol 3-kinase promotes tumor cell resistance to chemotherapeutic agents via a mechanism involving delay in cell cycle progression

McDonald, Gail T.; Sullivan, Richard; Paré, Geneviève C.; Graham, Charles H.

doi:10.1016/j.yexcr.2010.08.007

Cited by 36 publications

(22 citation statements)

References 34 publications

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“…This related G1-arrest phenomenonwhich led to inhibition of cell proliferation which was not necessarily associated with marked cell-death inductionhas also been seen with other PI3K inhibitors in a range of different carcinomas [37][38][39]. Here, modulation of the cycle regulatory proteins p21 and p27 by inhibition of the PI3K-AKT pathway may be a possible explanation, which has already been shown in breast, pancreatic and lung tumour cells [40,41].…”

Section: Discussionsupporting

confidence: 66%

Selective PI3K inhibition by BKM120 and BEZ235 alone or in combination with chemotherapy in wild-type and mutated human gastrointestinal cancer cell lines

Mueller

Bachmann

Linnig

et al. 2012

Cancer Chemother Pharmacol

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Section: Discussionsupporting

confidence: 66%

Selective PI3K inhibition by BKM120 and BEZ235 alone or in combination with chemotherapy in wild-type and mutated human gastrointestinal cancer cell lines

Mueller

Bachmann

Linnig

et al. 2012

Cancer Chemother Pharmacol

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“…First, none of the previous reports eliminate both proteins, which, according to our data, will allow normal p38MAPK activation. Second, the inactivation of ATM and/or ATR will probably affect other signaling pathways with critical roles in cell survival, such as the phosphatidylinositol 3-kinase/AKT Li and Yang, 2010;McDonald et al, 2010).…”

Section: Discussionmentioning

confidence: 99%

RETRACTED ARTICLE: P38MAPK is a major determinant of the balance between apoptosis and autophagy triggered by 5-fluorouracil: implication in resistance

et al. 2011

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5-Fluorouracil (5-FU), together with other drugs such as oxaliplatin, is one of the most important pharmacological agents in the treatment of colorectal cancer. Although mitogen-activated protein kinases (MAPKs) have been extensively connected with resistance to platinum compounds, no role has been established in 5-FU resistance. Here we demonstrate that p38MAPK activation is a key determinant in the cellular response to 5-FU. Thus, inhibition of p38MAPKa by SB203580 compound or by short-hairpin RNA interference-specific knockdown correlates with a decrease in the 5-FU-associated apoptosis and chemical resistance in both HaCaT and HCT116 cells. Activation of p38MAPK by 5-FU was dependent on canonical MAP2K, MAPK kinase (MKK)-3 and MKK6. In addition, ataxia telangiectasia mutated (ATM) and ataxia telangiectasia and Rad3 related (ATR) showed a redundancy of function for the final activation of p38MAPK. Resistance associated with p38MAPK inhibition correlates with an autophagic response that was mediated by a decrease in p53-driven apoptosis, without effect onto p53-dependent autophagy. Moreover, the results with colorectal cancer-derived cell lines with different p53 status and patterns of resistance to 5-FU suggest that de novo and acquired resistance was controlled by similar mechanisms. In summary, our data demonstrate a critical role for the p38MAPK signaling pathway in the cellular response to 5-FU by controlling the balance between apoptosis and autophagy.

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“…The molecules of AKT signalling pathway are often activated in many tumours resulting in malignant cell resistance to cancer therapies. Downregulation of AKT signalling usually sensitizes cells to chemotherapeutic treatments (Cheng et al 2005;Hers et al 2011;Hettinger et al 2007), although recent findings suggest also the opposite role of AKT in cell death (Ihle and Powis 2010;McDonald et al 2010;Suvasini and Somasundaram 2010). In this paper, we demonstrate the anti-death role of AKT signalling pathway in daunorubicin-induced muscle-derived stem cell apoptosis by using biochemical and genetic methods.…”

Section: Discussionmentioning

confidence: 75%

Daunorubicin induces cell death via activation of apoptotic signalling pathway and inactivation of survival pathway in muscle-derived stem cells

2012

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Daunorubicin (as well as other anthracyclines) is known to be toxic to heart cells and other cells in organism thus limiting its applicability in human cancer therapy. To investigate possible mechanisms of daunorubicin cytotoxicity, we used stem cell lines derived from adult rabbit skeletal muscle. Recently, we have shown that daunorubicin induces apoptotic cell death in our cell model system and distinctly influences the activity of MAP kinases. Here, we demonstrate that two widely accepted antagonistic signalling pathways namely proapoptotic JNK and prosurvival PI3K/AKT participate in apoptosis. Using the Western blot method, we observed the activation of JNK and phosphorylation of its direct target c-Jun along with inactivation of AKT and its direct target GSK in the course of programmed cell death. By means of small-molecule kinase inhibitors and transfection of cells with the genes of the components of these pathways, c-Jun and AKT, we confirm that JNK signalling pathway is proapoptotic, whereas AKT is antiapoptotic in daunorubicin-induced muscle cells. These findings could contribute to new approaches which will result in less toxicity and fewer side effects that are currently associated with the use of daunorubicin in cancer therapies.

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Inhibition of phosphatidylinositol 3-kinase promotes tumor cell resistance to chemotherapeutic agents via a mechanism involving delay in cell cycle progression

Cited by 36 publications

References 34 publications

Selective PI3K inhibition by BKM120 and BEZ235 alone or in combination with chemotherapy in wild-type and mutated human gastrointestinal cancer cell lines

Selective PI3K inhibition by BKM120 and BEZ235 alone or in combination with chemotherapy in wild-type and mutated human gastrointestinal cancer cell lines

RETRACTED ARTICLE: P38MAPK is a major determinant of the balance between apoptosis and autophagy triggered by 5-fluorouracil: implication in resistance

Daunorubicin induces cell death via activation of apoptotic signalling pathway and inactivation of survival pathway in muscle-derived stem cells

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