Role of insulin-like growth factor (IGF) axis in the development of tamoxifen resistance in breast cancer epithelial cells

The development of tamoxifen resistance (TamR) in oestrogen receptor positive (ER+) breast cancer is a major therapeutic challenge. Mechanisms suggested to ac-count for this have mainly focussed on the activation of alternative growth factor pathways. The insulin-like growth factor (IGF) axis is a prime candidate for investiga-tion in this area and the use of anti-IGF strategies in the clinical setting of tamoxifen resistance is under investigation. However such strategies, usually targeted to block the IGF-1 receptor (IGF-1R) have proved disappointing. The IGF axis is a multicom-ponent molecular system and the activity of IGF is modulated by the presence of six soluble high affinity IGF binding proteins (IGFBP 1-6). Given the potential role of the IGF axis in the development of tamoxifen resistance it is important to investigate whether the IGFBP family may play a role in this process opening up a route for alter-native anti-IGF based therapies. Using the ER+ MCF-7 cell line we demonstrated that five IGF axis genes (IGF-IR, IGF-2R, IGFBP-2, IGFBP-4 and IGFBP-5) were ex-pressed by both parental wt and tamoxifen resistant (TamR) MCF-7 cells with the re-maining genes (IGF-1, IGF-2, IGFBP-1, IGFBP-3 and IGFBP-6) either not expressed or expressed only at a very low level. IGFBP-5 expression was down-regulated by approximately 7-fold while IGFBP-2 was up-regulated by approximately 2-fold in TamR versus wt cells. These alterations in IGFBP-2 and IGFBP-5 gene expression were mirrored in protein levels measured in a conditioned medium by ELISA, Western and Ligand blot. Significantly, a knockdown of IGFBP-2 in TamR cells restored sensi-tivity to 4-hydroxytamoxifen (4-HT), reduced ERα expression to 45 ± 11.9% and en-hanced cell migration. Knock down of IGFBP-5 in wt cells had no effect on sensitivity to 4-HT but enhanced cell migration. Exogenous IGFBP-2 had no effect on tamoxifen sensitivity which may suggest an intracellular mechanism of action for IGFBP-2. Im-munohistochemical analysis of breast cancer tissue microarrays (TMAs) indicated that expression of IGFBP-2 was significantly associated with survival advantage in tamoxifen resistant patients

New insight into strategies used to develop long-acting G-CSF biologics for neutropenia therapy

Over the last 20 years, granulocyte colony-stimulating factors (G-CSFs) have become the major therapeutic option for the treatment of patients with neutropenia. Most of the current G-CSFs require daily injections, which are inconvenient and expensive for patients. Increased understanding of G-CSFs’ structure, expression, and mechanism of clearance has been very instrumental in the development of new generations of long-acting G-CSFs with improved efficacy. Several approaches to reducing G-CSF clearance via conjugation techniques have been investigated. PEGylation, glycosylation, polysialylation, or conjugation with immunoglobulins or albumins have successfully increased G-CSFs’ half-lives. Pegfilgrastim (Neulasta) has been successfully approved and marketed for the treatment of patients with neutropenia. The rapidly expanding market for G-CSFs has increased demand for G-CSF biosimilars. Therefore, the importance of this review is to highlight the principle, elimination’s route, half-life, clearance, safety, benefits, and limitations of different strategies and techniques used to increase the half-life of biotherapeutic G-CSFs. Understanding these strategies will allow for a new treatment with more competitive manufacturing and lower unit costs compared with that of Neulasta

Bax/Bcl-2 Cascade Is Regulated by the EGFR Pathway: Therapeutic Targeting of Non-Small Cell Lung Cancer

Non-small cell lung carcinoma (NSCLC) comprises 80%–85% of lung cancer cases. EGFR is involved in several cancer developments, including NSCLC. The EGFR pathway regulates the Bax/Bcl-2 cascade in NSCLC. Increasing understanding of the molecular mechanisms of fundamental tumor progression has guided the development of numerous antitumor drugs. The development and improvement of rationally planned inhibitors and agents targeting particular cellular and biological pathways in cancer have been signified as a most important paradigm shift in the strategy to treat and manage lung cancer. Newer approaches and novel chemotherapeutic agents are required to accompany present cancer therapies for improving efficiency. Using natural products as a drug with an effective delivery system may benefit therapeutics. Naturally originated compounds such as phytochemicals provide crucial sources for novel agents/drugs and resources for tumor therapy. Applying the small-molecule inhibitors (SMIs)/phytochemicals has led to potent preclinical discoveries in various human tumor preclinical models, including lung cancer. In this review, we summarize recent information on the molecular mechanisms of the Bax/Bcl-2 cascade and EGFR pathway in NSCLC and target them for therapeutic implications. We further described the therapeutic potential of Bax/Bcl-2/EGFR SMIs, mainly those with more potent and selectivity, including gefitinib, EGCG, ABT-737, thymoquinone, quercetin, and venetoclax. In addition, we explained the targeting EGFR pathway and ongoing in vitro and in vivo and clinical investigations in NSCLC. Exploration of such inhibitors facilitates the future treatment and management of NSCLC