Ricerc@Sapienza

Pain is one of the most common symptoms in children suffering from leukemia, who are often misdiagnosed with other childhood painful diseases such as juvenile idiopathic arthritis. Corticosteroid-induced osteonecrosis (ON) and vincristine-induced peripheral neuropathy (VIPN) are the most common painful manifestations. Additionally, ongoing pain may continue to impact quality of life in survivorship. This narrative review focuses on the pathophysiological mechanisms of pain in childhood leukemia and current available indications for analgesic treatments.

P-glycoprotein (P-gp) is a transmembrane efflux pump that has been associated with ineffective cancer chemotherapy and multidrug resistance (MDR). Chemical inhibitors of P-gp could have potential cancer therapeutic applications by preventing or reversing MDR. To exploit this, we designed twenty-five tetrahydroquinolinone analogs bearing pyridyl methyl carboxylate at C3 and different substituents at C4 as MDR reversal agents.

Notch signaling is considered a rational target in the therapy of several cancers, particularly those harbouring Notch gain of function mutations, including T-cell acute lymphoblastic leukemia (T-ALL). Although currently available Notch-blocking agents are showing anti-tumor activity in preclinical studies, they are not effective in all the patients and often cause severe side-effects, limiting their widespread therapeutic use.

Recent studies have uncovered an important role for RNA modifications in gene expression regulation, which led to the birth of the epitranscriptomics field. It is now acknowledged that RNA modifiers play a crucial role in the control of differentiation of stem and progenitor cells and that changes in their levels are a relevant feature of different types of cancer. To date, among more than 160 different RNA chemical modifications, the more relevant in cancer biology is the reversible and dynamic N6-methylation of adenosine, yielding N6-methyladenosine (m6A).

The involvement of sirtuins (SIRTs) in modulating metabolic and stress response pathways is attracting growing scientific interest. Some SIRT family members are located in mitochondria, dynamic organelles that perform several crucial functions essential for eukaryotic life. Mitochondrial dysfunction has emerged as having a key role in a number of human diseases, including cancer. Here, we investigated mitochondrial damage resulting from treatment with a recently characterized pan-SIRT inhibitor, MC2494.

Novel 3-aroyl-1,4-diarylpyrrole derivatives were synthesized to explore structure-activity relationships at the phenyls at positions 1 and 4 of the pyrrole. The presence of amino phenyl rings at positions 1 and 4 of the pyrrole ring were found to be a crucial requirement for potent antitumor activity. Several compounds strongly inhibited tubulin assembly through binding to the colchicine site. Compounds 42, 44, 48, 62 and 69 showed antitumor activity with low nanomolar IC50 values in several cancer cell lines.

Ibrutinib is a tyrosine kinase inhibitor used in the treatment of a variety of lymphoid malignancies, including chronic lymphocytic leukemia (CLL). Drugs inhibiting B-cell-receptor (BCR)-associated kinases, including BTK inhibitors, act on B cells and on a wide spectrum of tissues and cells, including innate immunity cells. Thus, alterations in the Bruton's tyrosine kinase (BTK) kinase function could lead to an impairment of innate immune cells functions and to an increased infectious risk in patients receiving BTK inhibitors.