Effective management of advanced cancer requires systemic treatment including small molecules that target unique features of aggressive tumor cells. At the same time, tumors are heterogeneous and current evidence suggests that a subpopulation of tumor cells, called tumor initiating or cancer stem cells, are responsible for metastatic dissemination, tumor relapse and possibly drug resistance. Classical apoptotic drugs are less effective against this critical subpopulation. In the course of generating a library of open-chain epothilones, we discovered a new class of small molecule anticancer agents that has no effect on tubulin but instead kills selected cancer cell lines by harnessing reactive oxygen species to induce ferroptosis. Interestingly, we find that drug sensitivity is highest in tumor cells with a mesenchymal phenotype. Furthermore, these compounds showed enhanced toxicity towards mesenchymal breast cancer populations with cancer stem cell properties
in vitro
. In summary, we have identified a new class of small molecule ferroptotic agents that warrant further investigation.
In the course of generating a library of open-chain epothilones, we discovered a new class of small molecule anticancer agents that has no effect on tubulin but instead kills selected cancer cell lines by harnessing reactive oxygen species in an iron-dependent manner. Results of the preliminary studies are consistent with the recently described cell death mechanism ferroptosis. Studies are in progress to confirm ferroptosis as the cell death mechanism and to identify the specific molecular targets of these small molecule anticancer agents.
ObjectiveMorbidity and mortality in Rheumatoid Arthritis (RA) is partly mitigated by maintaining immune and hematologic homeostasis. Identification of those at risk is challenging. Red cell distribution width (RDW) and absolute lymphocyte count (ALC) associate with cardiovascular disease (CVD) and mortality in the general population, and with disease activity in RA. How these parameters relate to inflammation and mortality in RA were investigated.MethodsIn a retrospective single VA-Rheumatology Clinic cohort of 327 RA patients treated with methotrexate (MTX)+/-TNF-blocker we evaluated RDW and ALC before and during therapy, and in relation to subsequent mortality. Findings were validated in a national VA cohort (n=13,914). In a subset of patients and controls we evaluated inflammatory markers.ResultsIn the local cohort, High RDW and Low ALC prior to MTX treatment each associated with subsequent mortality over 10 years (p<0.001 and p=0.004). The highest mortality was observed in those with both high-RDW and low ALC. This remained after adjusting for age and co-morbidities, and was validated in the national RA cohort. In the immunology cohort, soluble and cellular inflammatory markers were higher in RA than controls, ALC correlated with plasma TNFR2, NK/Monocyte-HLADR-MFI, and CD4CM/CD8CMHLADR/CD38%, while RDW associated with CD4%/CD8% and CD4EM/CD4TE HLADR/CD38%. MTX initiation was followed by an increase in RDW and decrease in ALC. TNF-blocker therapy added to MTX resulted in an increase in ALC.ConclusionRDW and ALC before DMARD therapy associate with biomarkers of monocyte/macrophage inflammation and subsequent mortality. Mechanistic linkage between TNF signaling and lymphopenia here warrants further investigation.
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