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Small-Molecule Targeted Therapies
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
At the molecular level, nilotinib has been shown to inhibit kinases including Bcr-Abl, Kit, Lck, EPHA3, EPHA8, DDR1, DDR2, PDGFRB, MAPK11, and ZAK. However, it does not inhibit the Src kinase, a key regulator of other tyrosine kinase proteins that influence whether cells proliferate or die. The binding of nilotinib to its target Bcr-Abl protein is energetically more favorable than that of imatinib, and it has been shown to have an approximately 20-fold increase in potency compared to imatinib in in vitro kinase inhibition and cellular proliferation assays.
Non-Hodgkin Lymphoma
Published in Tariq I. Mughal, Precision Haematological Cancer Medicine, 2018
Cutaneous T-cell lymphomas (CTCL) demonstrate extensive genomic heterogeneity with mutations in genome maintenance and DNA repair, which overlaps with other mature T-cell lymphomas. The 55 driver genes identified so far include epigenetic regulation (DNMT3, ASLX3, TET1, TET2, TET3), homologous recombination (RAD51C, BRCA2, POLD1), telomerase maintenance (POT1, ATM) and 5 which, such as RGD, were previously not recognized to be associated with cancer. In addition, consistent somatic copy number variants (CNVs) involving other putative genes comprise >90% of all driver mutations. The principal cellular signalling pathways involved include TCR/NF-kB, MAPK, JAK-STAT, ERK and PDGFR. Other important observations include mutations in PRKCQ (20%), indicative of the recruitment of the TCR/NF-kB pathway and PLCG1 (11%). In patients with Sézary syndrome (SS), a leukaemic variant of CTCL, driver genes include POT1, TP53, ARID1A, CTCF and DNMT3A, as well as two unique mutations, PLCG1 and BRCA2. Additional novel targets for intervention include MAPK11/p38β, which appears to be a principal driver in SS, and IL-13 which functions as an autocrine growth factor in CTCL.
Advances in adrenocortical carcinoma pharmacotherapy: what is the current state of the art?
Published in Expert Opinion on Pharmacotherapy, 2022
Valentina Cremaschi, Andrea Abate, Deborah Cosentini, Salvatore Grisanti, Elisa Rossini, Marta Laganà, Mariangela Tamburello, Antonella Turla, Sandra Sigala, Alfredo Berruti
As a relevant number of receptor tyrosine kinases were frequently found overexpressed in ACC [41], many preclinical ACC papers were focused on other tyrosine kinases inhibitors (TKIs). A recent study showed that sorafenib, an anti-angiogenetic drug, is able to induce apoptosis in NCI-H295R cells; however, authors did not recommend its use in patients with ACC, as a proportion of cells survived the cytotoxic effect of the drug [42]. Interesting data came from a study that evaluated the effect of another TKI, nilotinib, a multi targeted drug which inhibits the kinases BCR-ABL, KIT, LCK, EPHA3, EPHA8, DDR1, DDR2, PDGFRB, MAPK11, and ZAK. In in vitro models of ACC, using both 2D and 3D cell cultures, authors demonstrated that mitotane was less effective in 3D compared to 2D NCI-H295R cells, while nilotinib cytotoxic effect was superimposable in the two experimental cell models [43]. Interestingly, the 3D cultures represent an evolution of 2D cultures, toward a better, albeit simplified, representation of the in vivo setting, useful for drug screening.
Immunogenetic effects of low dose (CEM43 30) magnetic nanoparticle hyperthermia and radiation in melanoma cells
Published in International Journal of Hyperthermia, 2019
Kayla E. A. Duval, Nicholas A. Vernice, Robert J. Wagner, Steven N. Fiering, James D. Petryk, Gabriela J. Lowry, Steven S. Tau, John Yin, Georgia R. Houde, Aneeq S. Chaudhry, P. Jack Hoopes
Virtually all of the cell death pathways activated by mNPH were activated to a greater extent by the combined mNPH + radiation treatment. Genes such as ERK2, CASP3, MAPK11 (p38b), Fas and PUMA demonstrated significantly enhanced expression. As with mNPH alone, decreases in ERK2 and MAPK11 expression, following mNPH + radiation could demonstrate a reduction in tumor cell survival signaling through the p38/MAPK pathway. Greater increases in PUMA expression, a well-known pro-apoptotic gene, along with an increase in cell death receptor Fas, demonstrate enhanced activation of the apoptotic cascades following mNPH + radiation to activate to a greater degree than mNPH or radiation.
A novel anti-platelet aggregation target of chinensinaphthol methyl ether and neojusticin B obtained from Rostellularia procumbens (L.) Nees
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2019
Songtao Wu, Yanfang Yang, Bo Liu, Zhoutao Xie, Weichen Xiong, Pengfei Hao, Wenping Xiao, Yuan Sun, Zhongzhu Ai, Hezhen Wu
Compared with the control group, hundreds of genes were revealed to be differentially expressed in platelet in the EtOAc extract group (Table 1). In EtOAc extract group, PLCB2, PRKCA, GNAQ, MAPK10, MAPK8, MAPK11, MAPK14, GNAI2, PIK3CG, and PIK3R1 were markedly underexpressed in the liver tissues of the model group compared with the control group.