ABSTRACT
Cancer cell proliferation relies on the ability of cancer cells to grow, transition through the cell cycle, and divide. To identify novel chemical probes for dissecting the mechanisms governing cell cycle progression and cell division, and for developing new anti-cancer therapeutics, we developed and performed a novel cancer cell-based high-throughput chemical screen for cell cycle modulators. This approach identified novel G1, S, G2, and M-phase specific inhibitors with drug-like properties and diverse chemotypes likely targeting a broad array of processes. We further characterized the M-phase inhibitors and highlight the most potent M-phase inhibitor MI-181, which targets tubulin, inhibits tubulin polymerization, activates the spindle assembly checkpoint, arrests cells in mitosis, and triggers a fast apoptotic cell death. Importantly, MI-181 has broad anti-cancer activity, especially against BRAF(V600E) melanomas.
Subject(s)
Antineoplastic Agents/pharmacology , Cell Cycle/drug effects , Drug Discovery , High-Throughput Screening Assays/methods , Molecular Probes/pharmacology , Antineoplastic Agents/therapeutic use , Cell Death/drug effects , HeLa Cells , Humans , M Phase Cell Cycle Checkpoints/drug effects , Mitosis/drug effects , Neoplasms/drug therapy , Phenotype , Polymerization/drug effects , Small Molecule Libraries/analysis , Small Molecule Libraries/pharmacology , Tubulin/metabolismABSTRACT
The cancer of unknown primary (CUP) concept encompasses a heterogeneous group of cancers that are difficult to diagnose and that show diverse clinical and histopathological features. Currently, CUP is the fifth most frequent cancer diagnosis in women and the eighth in men. The ongoing development of new therapies specific to the various cancer types makes mandatory the identification of the primary tumour in CUP patients, so that they may benefit from advances in therapy and improvements in prognosis. Molecular detection techniques provide very useful tools in the prediction of primary tumour types and must be used together with clinical, histopathological and IHC diagnostic techniques. Steady collaboration and fluid communication between oncologists and pathologists is of the utmost importance for the correct interpretation of tests and the personalised approach required by each individual case. Work in multidisciplinary teams will result in significant changes in the diagnosis and treatment of these patients (AU)
Subject(s)
Humans , Male , Female , Diagnostic Imaging/methods , Diagnostic Imaging , Neoplasms, Unknown Primary/diagnosis , Neoplasms, Unknown Primary/metabolism , PrognosisABSTRACT
Unknown primary cancer (UPC) is a common clinical syndrome classically associated with a poor prognosis. Pathological examination including immunohistochemistry continues to be essential in tumour origin characterization, although in many cases primary tumour site remains unknown. Gene expression based analysis may offer important diagnostic information that could lead to therapeutic decisions (AU)