Involvement of Akt-1 and mTOR in Sensitivity of Breast Cancer to Targeted Therapy

Elucidating the response of breast cancer cells to chemotherapeutic and hormonal based drugs is clearly important as these are frequently used therapeutic approaches. A signaling pathway often involved in chemo- and hormonal-resistance is the Ras/PI3K/PTEN/Akt/mTOR cascade. In the studies presented in this report, we have examined the effects of constitutive activation of Akt on the sensitivity of MCF-7 breast cancer cells to chemotherapeutic- and hormonal-based drugs as well as mTOR inhibitors. MCF-7 cells which expressed a constitutively-activated Akt-1 gene [ΔAkt-1(CA)] were more resistant to doxorubicin, etoposide and 4-OH-tamoxifen (4HT) than cells lacking ΔAkt-1(CA). Cells which expressed ΔAkt-1(CA) were hypersensitive to the mTOR inhibitor rapamycin. Furthermore, rapamycin lowered the IC50s for doxorubicin, etoposide and 4HT in the cells which expressed ΔAkt-1(CA), demonstrating a potential improved method for treating certain breast cancers which have deregulated PI3K/PTEN/Akt/mTOR signaling. Understanding how breast cancers respond to chemo- and hormonal-based therapies and the mechanisms by which they can become drug resistant may enhance our ability to treat breast cancer. These results also document the potential importance of knowledge of the mutations present in certain cancers which may permit more effective therapies

Exploiting p53 Status to Enhance Effectiveness of Chemotherapy by Lowering Associated Toxicity

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The Cultural Construction of the Maine Sporting Camps

Maine’s lakes and forests attracted a growing number of urban hunters and anglers after 1880. Attracted in part by the informality and remoteness of the Maine woods, these urban recreationists nevertheless imposed their own sense of order and propriety upon the culture of the sporting camp. Urban “sports “ went “back to nature, ” yet maintained their status - and their social distance - as ladies and gentlemen.

Targeting signaling and apoptotic pathways involved in chemotherapeutic drug-resistance of hematopoietic cells

A critical problem in leukemia as well as other cancer therapies is the development of chemotherapeutic drug-resistance. We have developed models of hematopoietic drug resistance that are based on expression of dominant-negative TP53 [TP53 (DN)] or constitutively-active MEK1 [MEK1(CA)] oncogenes in the presence of chemotherapeutic drugs. In human cancer, functional TP53 activity is often lost in human cancers. Also, activation of the Raf/MEK/ERK pathway frequently occurs due to mutations/ amplification of upstream components of this and other interacting pathways. FL5.12 is an interleukin-3 (IL−3) dependent hematopoietic cell line that is sensitive to doxorubicin (a.k.a Adriamycin). FL/Doxo is a derivative cell line that was isolated by culturing the parental FL5.12 cells in doxorubicin for prolonged periods of time. FL/Doxo + TP53 (DN) and FL/Doxo + MEK1 (CA) are FL/Doxo derivate cell lines that were infected with retrovirus encoding TP53 (DN) or MEK1 (CA) and are more resistant to doxorubicin than FL/Doxo cells. This panel of cell lines displayed differences in the sensitivity to inhibitors that suppress mTORC1, BCL2/BCLXL, MEK1 or MDM2 activities, as well as, the proteasomal inhibitor MG132. The expression of key genes involved in cell growth and drug-resistance (e.g., MDM2, MDR1, BAX) also varied in these cells. Thus, we can begin to understand some of the key genes that are involved in the resistance of hematopoietic cells to chemotherapeutic drugs and targeted therapeutics

Recent discoveries in the cycling, growing and aging of the p53 field

The P53 gene and it product p53 protein is the most studied tumor suppressor, which was considered as oncogene for two decades until 1990. More than 60 thousand papers on the topic of p53 has been abstracted in Pubmed. What yet could be discovered about its role in cell death, growth arrest and apoptosis, as well as a mediator of the therapeutic effect of anticancer drugs. Still during recent few years even more amazing discoveries have been done. Here we review such topics as suppression of epigenetic silencing of a large number of non-coding RNAs, role of p53 in suppression of the senescence phenotype, inhibition of oncogenic metabolism, protection of normal cells from chemotherapy and even tumor suppression without apoptosis and cell cycle arrest

Targeting the phosphatidylinositol 3-kinase/Akt/mechanistic target of rapamycin signaling pathway in B-lineage acute lymphoblastic leukemia: An update

Despite considerable progress in treatment protocols, B-lineage acute lymphoblastic leukemia (B-ALL) displays a poor prognosis in about 15–20% of pediatric cases and about 60% of adult patients. In addition, life-long irreversible late effects from chemo- and radiation therapy, including secondary malignancies, are a growing problem for leukemia survivors. Targeted therapy holds promising perspectives for cancer treatment as it may be more effective and have fewer side effects than conventional therapies. The phosphatidylinositol 3-phosphate kinase (PI3K)/Akt/mechanistic target of rapamycin (mTOR) signaling pathway is a key regulatory cascade which controls proliferation, survival and drug-resistance of cancer cells, and it is frequently upregulated in the different subtypes of B-ALL, where it plays important roles in the pathophysiology, maintenance and progression of the disease. Moreover, activation of this signaling cascade portends a poorer prognosis in both pediatric and adult B-ALL patients. Promising preclinical data on PI3K/Akt/mTOR inhibitors have documented their anticancer activity in B-ALL and some of these novel drugs have entered clinical trials as they could lead to a longer event-free survival and reduce therapy-associated toxicity for patients with B-ALL. This review highlights the current status of PI3K/Akt/mTOR inhibitors in B-ALL, with an emphasis on emerging evidence of the superior efficacy of synergistic combinations involving the use of traditional chemotherapeutics or other novel, targeted agents

Recent progress in targeting cancer

In recent years, numerous new targets have been identified and new experimental therapeutics have been developed. Importantly, existing non-cancer drugs found novel use in cancer therapy. And even more importantly, new original therapeutic strategies to increase potency, selectivity and decrease detrimental side effects have been evaluated. Here we review some recent advances in targeting cancer

Increased Akt signaling resulting from the loss of androgen responsiveness in prostate cancer

The mechanisms responsible for the switch of prostate cancer from androgen-sensitive (AS) to androgen-insensitive (AI) form are not well understood. Regulation of androgen receptor (AR), through which androgens control the expression of genes involved in prostate cells proliferation, migration and death also involves its cross-talk with the other signaling pathways, transcription factors and coregulatory proteins, such as β-catenin. With the aim to determine their possible contribution in triggering the switch from AS to AI form, which occurs upon androgen deprivation therapy - AR, Akt and β-catenin expression were knocked-down with respective siRNAs. Treatment of LNCaP prostate cells with siRNA for AR significantly reduced their proliferation (45-70%), expression of nuclear β- catenin, cyclin-D1, cyclin-G1, c-Myc as well as activity of metalloproteinases (MMPs) -2,-7,-9 and cell migration. Surprisingly, after longer (over 72 hrs) silencing of AR in LNCaP cells, elevated levels of p-Akt were detected and enhanced proliferation as well as expression of nuclear β-catenin, cyclin-D1, c-Myc and activity of MMPs were observed. Such effects were not observed in either PC-3 or DU145 AI cells. However, silencing of Akt and /or β-catenin in those as well as in LNCaP cells led to their decreased proliferation and migration. Our findings suggest that in prostate cancer cells, either AR or Akt signaling prevails, depending on their initial androgen sensitivity and its availability. In AI prostate cancer cells, Akt takes over the role of AR and more effectively contributes through the same signaling molecule, β-catenin, to AI cancer progression

Harnessing the PI3K/Akt/mTOR pathway in T-cell acute lymphoblastic leukemia: Eliminating activity by targeting at different levels

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive malignant hematological disorder arising in the thymus from T-cell progenitors. T-ALL mainly affects children and young adults, and remains fatal in 20% of adolescents and 50% of adults, despite progress in polychemotherapy protocols. Therefore, innovative targeted therapies are desperately needed for patients with a dismal prognosis. Aberrant activation of PI3K/Akt/mTOR signaling is a common event in T-ALL patients and portends a poor prognosis. Preclinical studies have highlighted that modulators of PI3K/Akt/mTOR signaling could have a therapeutic relevance in T-ALL. However, the best strategy for inhibiting this highly complex signal transduction pathway is still unclear, as the pharmaceutical companies have disclosed an impressive array of small molecules targeting this signaling network at different levels. Here, we demonstrate that a dual PI3K/PDK1 inhibitor, NVP-BAG956, displayed the most powerful cytotoxic effects against T-ALL cell lines and primary patients samples, when compared with a pan class I PI3K inhibitor (GDC-0941), an allosteric Akt inhibitor (MK-2206), an mTORC1 allosteric inhibitor (RAD-001), or an ATP-competitive mTORC1/mTORC2 inhibitor (KU-63794). Moreover, we also document that combinations of some of the aforementioned drugs strongly synergized against T-ALL cells at concentrations well below their respective IC50. This observation indicates that vertical inhibition at different levels of the PI3K/Akt/mTOR network could be considered as a future innovative strategy for treating T-ALL patients