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Synthetic Compounds vs. Phytochemicals for the Treatment of Human Cutaneous Malignant Melanoma
Published in Namrita Lall, Medicinal Plants for Cosmetics, Health and Diseases, 2022
Jacqueline Maphutha, Namrita Lall
The tumor microenvironment is made up of cancer-associated fibroblasts, tumor associated macrophages, adipocytes, endothelial cells, immune cells and the extracellular matrix (Franco et al., 2020). PI3K inhibitors are largely used to target cancer cells specifically those that trigger apoptosis; however, the mechanism is largely affected by the development of resistance. Okkenhaug, Graupera, and Vanhaesebroeck (2016) suggested that isoform-selective PI3K inhibitors administered for a short period of time, i.e. three days, could enhance the functioning of blood vessels that supply nutrients and oxygen to the tumors. Improving the function of blood vessels through the downregulation of vascular endothelial growth factor (VEGF) enables effective drug delivery (chemotherapeutics, immunotherapy and targeted therapy) (Okkenhaug, Graupera, and Vanhaesebroeck, 2016).
Small-Molecule Targeted Therapies
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
The PI3K (Phosphatidylinositol 3-Kinase) pathway (Figure 6.87), also known as the PI3K/AKT/mTOR pathway, is an intricate signaling cascade activated by growth factors binding to the relevant RTK (Receptor Tyrosine Kinase) receptors on the cell surface. The pathway is important in both healthy and tumor cells, as it regulates a number of key cellular functions including metabolism, proliferation, and survival. However, it is one of the most frequently dysregulated signaling pathways in tumor cells due to mutation of one or more of the key proteins in the pathway, and is usually activated inappropriately rather than de-activated. Abnormally activated PI3K signaling can lead to uncontrolled proliferation, enhanced cell survival, and greater cancer cell motility.
Nanomaterials for Theranostics: Recent Advances and Future Challenges *
Published in Valerio Voliani, Nanomaterials and Neoplasms, 2021
Eun-Kyung Lim, Taekhoon Kim, Soonmyung Paik, Seungjoo Haam, Yong-Min Huh, Kwangyeol Lee
Therefore, hyperactivation of the PI3K/Akt pathway is often genetically selected during tumorigenesis, and the normal cellular functions regulated by this pathway are recruited to promote proliferation and survival suppressor function. Through reciprocal regulation of the PI3K/Akt pathway and the tumor suppressor protein p53, Akt can promote p53 degradation by phosphorylating and activation of murine double minute 2 (MDM2), an important negative regulator of the p53 tumor suppressor [182]. Therefore, blocking this pathway could simultaneously inhibit the proliferation of tumor cells and sensitize them toward apoptosis. In addition, hyperactivation of the PI3K/Akt pathway is found in a wide range of tumors leading to tumor cell transformation and resistance to chemotherapeutic agents. Thus, blockage of these pathways might be sufficient to inhibit tumor growth. The available clinical evidence of PI3K pathways deregulating in various cancers and identification of downstream kinases that are involved in mediating the effects of PI3K (Akt and phosphoinositide-dependent kinase-1 [PDK1]) provides potential targets for development of small-molecule therapies [170–173, 175–177, 182, 186–194].
Inhibitors of phosphoinositide 3-kinase (PI3K) and phosphoinositide 3-kinase-related protein kinase family (PIKK)
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2023
Xueqin Huang, Li You, Eugenie Nepovimova, Miroslav Psotka, David Malinak, Marian Valko, Ladislav Sivak, Jan Korabecny, Zbynek Heger, Vojtech Adam, Qinghua Wu, Kamil Kuca
AKT is an indispensable part of PI3K-mediated signalling and its activation can phosphorylate a variety of kinases and transcription factors, thereby affecting cellular functions. For example, the phosphorylation of TSC2 by AKT can inhibit the GTPase activity of the TSC1/TSC2 complex, leading to the accumulation of Rheb-GTP and subsequent mTORC1 activation179. AKT phosphorylates Glycogen synthase kinase-3β to facilitate glucose metabolism249. AKT is able to activate the inhibitor of kappa B kinase (IKK), which is involved in the modulation of IκBα. Phosphorylated IκBα is rapidly degraded to release NF-κB, and the released NF-kB translocates to the nucleus and induces the expression of target genes, thus playing an important role in promoting tumour survival3. AKT phosphorylates forkhead box protein O1, inhibiting its nuclear translocation and preventing its transcriptional activation250. AKT phosphorylates the ubiquitin ligase MDM2 (mouse double microgene 2) and translocates it to the nucleus to bind to p53, thereby affecting cell survival by increasing the degradation of the p53 protein251. AKT activation is closely related to the development and progression of various tumours, so suppressing AKT may be an excellent therapeutic approach.
Phosphatidylinositol 3-kinase (PI3K) inhibitors: a recent update on inhibitor design and clinical trials (2016–2020)
Published in Expert Opinion on Therapeutic Patents, 2021
Dima A. Sabbah, Rima Hajjo, Sanaa K. Bardaweel, Haizhen A. Zhong
The PI3K/AKT/mTOR pathway plays a central role in regulating cell growth and proliferation and thus has been considered as an effective anticancer drug target. Many PI3K inhibitors have been developed and progressed to various stages of clinical trials and some have even been approved by the regulatory agency as anticancer treatment. Due to the gain-of-function of PI3Kα mutants (E542K, E545K, and H1047R), it is highly desirable to design and develop mutant-specific PI3K inhibitors. Our previous studies showed that by employing residues that are responsible for subtype-specific or mutant-specific binding, it is possible to design inhibitors that are specific to either PI3Kα subtype or γ subtype, or even PI3Kα H1047R mutant-specific [79,115]. Similarly, PI3Kγ-selective inhibitors could be designed by using Lys883 during drug design [119]. To enhance selectivity of future drugs, it would be important to focus on structure-based drug design by taking advantage of the structural features that are specific to the subtypes or mutants of PI3K.
An evaluation of buparlisib for the treatment of head and neck squamous cell carcinoma
Published in Expert Opinion on Pharmacotherapy, 2021
Nicholas Lenze, Bhisham Chera, Siddharth Sheth
PI3K enzymes are categorized into three classes according to structure, substrate preference, and function. Class I PI3Ks are heterodimers consisting of a regulatory subunit and a catalytic subunit. These are further subcategorized by their catalytic subunits: class IA (PI3Kα, PI3Kβ, PI3Kδ) or class IB (PI3Kγ) [9,10]. Class IA consists of three catalytic subunits isoforms (p110α, p110β, and p110δ) which are encoded by PIK3CA, PIK3CB, and PIK3CD, respectively. Class IA has five variants of the regulatory subunit: p85α, p55α, p50α, p85β, and p55δ. Class IB consists of the catalytic subunit (p110γ), which is encoded by PIK3CG. Class IB has two variants of the regulatory subunit: p101 and p76. Class II PI3Ks are monomers of catalytic isoforms and lack regulatory subunits. Class II PI3Ks are involved in angiogenesis, endocytosis, and insulin stimulation [11]. Class III PI3Ks are heterodimers of the catalytic regulatory subunit, and they convert phosphatidylinositol (PI) to phosphatidylinositol 3-phosphate (PI3P). The Class III PI3Ks function in autophagy induction [12].