Targeting GSK3 and Associated Signaling Pathways Involved in Cancer

Glycogen synthase kinase 3 (GSK-3) is a serine/threonine (S/T) protein kinase. Although GSK-3 originally was identified to have functions in regulation of glycogen synthase, it was subsequently determined to have roles in multiple normal biochemical processes as well as various disease conditions. GSK-3 is sometimes referred to as a moonlighting protein due to the multiple substrates and processes which it controls. Frequently, when GSK-3 phosphorylates proteins, they are targeted for degradation. GSK-3 is often considered a component of the PI3K/PTEN/AKT/GSK-3/mTORC1 pathway as GSK-3 is frequently phosphorylated by AKT which regulates its inactivation. AKT is often active in human cancer and hence, GSK-3 is often inactivated. Moreover, GSK-3 also interacts with WNT/\u3b2-catenin signaling and \u3b2-catenin and other proteins in this pathway are targets of GSK-3. GSK-3 can modify NF-\u3baB activity which is often expressed at high levels in cancer cells. Multiple pharmaceutical companies developed small molecule inhibitors to suppress GSK-3 activity. In addition, various natural products will modify GSK-3 activity. This review will focus on the effects of small molecule inhibitors and natural products on GSK-3 activity and provide examples where these compounds were effective in suppressing cancer growth

Exploiting p53 status to enhance effectiveness of chemotherapy by lowering associated toxicity.

Questo articolo non ha abstrac

Chemotherapy for breast cancer

Breast cancer ranks as the second most common cause of cancer death among women in the United States. Only lung cancer, which results primarily from cigarette smoking, induces more cancer deaths in women in the USA. Approximately 1 in 7 women in the United States will be diagnozed with breast cancer during her lifetime. Over 210,000 new cases of breast cancer are diagnozed in the United States each year. Breast cancer is the cause of death of over 40,000 women in the United States each year. Many drugs have been demonstrated to extend survival of breast cancer patients. Anticancer agents frequently used to treat breast cancer include chemotherapeutic drugs such as methotrexate, 5-fluorouracil (5-FU), cyclophosphamide, anthracyclines, taxanes, monoclonal antibodies such as trastuzumab, hormonal based therapeutics such as tamoxifen and aromatase inhibitors. Mechanisms by which these agents inhibit breast cancer progression vary from drug to drug. While these drugs are the mainstay of chemo, immuno and hormonal therapy of breast cancer, a common problem with these treatments is the development of drug resistance. Breast cancer cells can become drug resistant by multiple mechanisms which include: increased expression of membrane transporters which transport the toxic drug out of the cell or modify/detoxify the drug, increased expression of signaling and anti-apoptotic pathways as well as other mechanisms which allow the cells to grow in the presence of the drug. This manuscript will discuss some of the mechanisms by which the altered expression of key signaling and apoptotic pathways may lead to breast cancer drug resistance and how targeting these pathways may result in the suppression of neoplastic growth

The therapeutic potential of mTOR inhibitors in breast cancer.

Rapamycin and modified rapamycins (rapalogs) have been used to prevent allograft rejection after organ transplant for over 15 years. The mechanistic target of rapamycin (mTOR) has been determined to be a key component of the mTORC1 complex which consists of the serine/threonine kinase TOR and at least five other proteins which are involved in regulating its activity. Some of the best characterized substrates of mTORC1 are proteins which are key kinases involved in the regulation of cell growth (e.g., p70S6K) and protein translation (e.g., 4E-BP1). These proteins may in some cases serve as indicators to sensitivity to rapamycin-related therapies. Dysregulation of mTORC1 activity frequently occurs due to mutations at, or amplifications of, upstream growth factor receptors (e.g., human epidermal growth factor receptor-2, HER2) as well as kinases (e.g., PI3K) and phosphatases (e.g., PTEN) critical in the regulation of cell growth. More recently, it has been shown that certain rapalogs may enhance the effectiveness of hormonal-based therapies for breast cancer patients who have become resistant to endocrine therapy. The combined treatment of certain rapalogs (e.g., everolimus) and aromatase inhibitors (e.g., exemestane) has been approved by the United States Food and Drug Administration (US FDA) and other drug regulatory agencies to treat estrogen receptor positive (ER+) breast cancer patients who have become resistant to hormonal-based therapies and have progressed. This review will summarize recent basic and clinical research in the area and evaluate potential novel therapeutic approaches

Increased NGAL (Lnc2) expression after chemotherapeutic drug treatment.

Identifying the pathways activated and critical for cancer initiation and subsequent spread (invasion and metastasis) are essential for improved cancer therapies. Over the past 35 years, many genes have been identified which can cause or contribute to cancer. These include two major classes of genes, oncogenes and tumor suppressor genes. In some cases the genetic culprit involved in a particular cancer may be known, however, in most cases there are multiple genetic and epigenetic events occurring simultaneously which can interact and result in cancer cell formation and metastasis. In addition, there are other important contributions by the tumor microenvironment which can lead to the progression of cancer as well as resistance to various therapeutic approaches

Enhancing therapeutic efficacy by targeting non-oncogene addicted cells with combinations of signal transduction inhibitors and chemotherapy.

The effects of inhibition of the Raf/MEK/ERK and PI3K/Akt/mTOR signaling pathways and chemotherapeutic drugs on cell cycle progression and drug sensitivity were examined in cytokine-dependent FL5.12 hematopoietic cells. We examined their effects, as these cells resemble normal hematopoietic precursor cells as they do not exhibit “oncogene-addicted” growth, while they do display “cytokine-addicted” proliferation as cytokine removal resulted in apoptosis in greater than 80% of the cells within 48 h. When cytokine-dependent FL5.12 cells were cultured in the presence of IL-3, which stimulated multiple proliferation and anti-apoptotic cascades, MEK, PI3K and mTOR inhibitors transiently suppressed but did not totally inhibit cell cycle progression or induce apoptosis while chemotherapeutic drugs such as doxorubicin and paclitaxel were more effective in inducing cell cycle arrest and apoptosis. Doxorubicin induced a G(1) block, while paclitaxel triggered a G(2)/M block. Doxorubicin was more effective in inducing cell death than paclitaxel. Furthermore the effects of doxorubicin could be enhanced by addition of MEK, PI3K or mTOR inhibitors. Cytokine-dependent cells which proliferate in vitro and are not “oncogene-addicted” may represent a pre-malignant stage, more refractory to treatment with targeted therapy. However, these cells are sensitive to chemotherapeutic drugs. It is important to develop methods to inhibit the growth of such cytokine-dependent cells as they may resemble the leukemia stem cell and other cancer initiating cells. These results demonstrate the enhanced effectiveness of targeting early hematopoietic progenitor cells with combinations of chemotherapeutic drugs and signal transduction inhibitors

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 MCF7 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 [.Akt-1(CA)] were more resistant to doxorubicin, etoposide and 4-OH-tamoxifen (4HT) than cells lacking.Akt-1(CA). Cells which expressed Delta Akt-1(CA) were hypersensitive to the mTOR inhibitor rapamycin. Furthermore, rapamycin lowered the IC(50)s for doxorubicin, etoposide and 4HT in the cells which expressed Delta Akt-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

Therapeutic resistance in breast cancer cells can result from deregulated EGFR signaling

The epidermal growth factor receptor (EGFR) interacts with various downstream molecules including phospholipase C (PLC)/protein kinase C (PKC), Ras/Raf/MEK/ERK, PI3K/PTEN/Akt/GSK-3, Jak/STAT and others. Often these pathways are deregulated in human malignancies such as breast cancer. Various therapeutic approaches to inhibit the activity of EGFR family members including small molecule inhibitors and monoclonal antibodies (MoAb) have been developed. A common problem with cancer treatments is the development of drug-resistance. We examined the effects of a conditionally-activated EGFR (v-Erb-B:ER) on the resistance of breast cancer cells to commonly used chemotherapeutic drugs such as doxorubicin, daunorubicin, paclitaxel, cisplatin and 5-flurouracil as well as ionizing radiation (IR). v-Erb-B is similar to the EGFR-variant EGFRvIII, which is expressed in various cancers including breast, brain, prostate. Both v-Erb-B and EGFRvIII encode the EGFR kinase domain but lack key components present in the extracellular domain of EGFR which normally regulate its activity and ligand-dependence. The v-Erb-B oncogene was ligated to the hormone binding domain of the estrogen receptor (ER) which results in regulation of the activity of the v-Erb-ER construct by addition of either estrogen (E2) or 4-hydroxytamoxifen (4HT) to the culture media. Introduction of the v-Erb-B:ER construct into the MCF-7 breast cancer cell line increased the resistance to the cells to various chemotherapeutic drugs, hormonal-based therapeutics and IR. These results point to the important effects that aberrant expression of EGFR kinase domain can have on therapeutic resistance