Summary
Most forms of chemotherapy employ mechanisms involving induction of oxidative stress, a strategy that can be effective due to the elevated oxidative state commonly observed in cancer cells. However, recent studies have shown that relative redox levels in primary tumors can be heterogeneous, suggesting that regimens dependent on differential oxidative state may not be uniformly effective. To investigate this issue in hematological malignancies, we evaluated mechanisms controlling oxidative state in primary specimens derived from acute myelogenous leukemia (AML) patients. Our studies demonstrate three striking findings. First, the majority of functionally-defined leukemia stem cells (LSCs) are characterized by relatively low levels of reactive oxygen species (termed “ROS-low”). Second, ROS-low LSCs aberrantly over-express BCL-2. Third, BCL-2 inhibition reduced oxidative phosphorylation and selectively eradicated quiescent LSCs. Based on these findings, we propose a model wherein the unique physiology of ROS-low LSCs provides an opportunity for selective targeting via disruption of BCL-2-dependent oxidative phosphorylation.
Background: Eradication of primary human leukemia cells represents a major challenge. Therapies have not substantially changed in over 30 years. Results: Using normal versus leukemia specimens enriched for primitive cells, we document aberrant regulation of glutathione metabolism. Conclusion: Aberrant glutathione metabolism is an intrinsic property of human leukemia cells. Significance: Interventions based on modulation of glutathione metabolism represent a powerful means to improve therapy.
• Using AML as a model, we investigated the effect of treatment and disease evolution on functionally defined cancer stem cell populations.• We demonstrate large-scale changes in LSC frequency and phenotype after relapse, best described using highdimensional space analyses.Most cancers evolve over time as patients initially responsive to therapy acquire resistance to the same drugs at relapse. Cancer stem cells have been postulated to represent a therapy-refractory reservoir for relapse, but formal proof of this model is lacking. We prospectively characterized leukemia stem cell populations (LSCs) from a well-defined cohort of patients with acute myelogenous leukemia (AML) at diagnosis and relapse to assess the effect of the disease course on these critical populations. Leukemic samples were collected from patients with newly diagnosed AML before therapy and after relapse, and LSC frequency was assessed by limiting dilution analyses. LSC populations were identified using fluorescent-labeled cell sorting and transplantation into immunodeficient NOD/SCID/interleukin 2 receptor g chain null mice. The surface antigen expression profiles of pretherapy and postrelapse LSCs were determined for published LSC markers. We demonstrate a 9-to 90-fold increase in LSC frequency between diagnosis and relapse. LSC activity at relapse was identified in populations of leukemic blasts that did not demonstrate this activity before treatment and relapse. In addition, we describe genetic instability and exceptional phenotypic changes that accompany the evolution of these new LSC populations. This study is the first to characterize the evolution of LSCs in vivo after chemotherapy, identifying a dramatic change in the physiology of primitive AML cells when the disease progresses. Taken together, these findings provide a new frame of reference by which to evaluate candidate AML therapies in which both disease control and the induction of more advanced forms of disease should be considered. (Blood. 2016;128(13):1671-1678
The sesquiterpene lactone parthenolide has recently attracted
considerable attention owing to its promising antitumor properties, in
particular in the context of stem-cell cancers including leukemia. Yet, the lack
of viable synthetic routes for reelaborating this complex natural product have
represented a fundamental obstacle toward further optimization of its
pharmacological properties. Here, we demonstrate how this challenge could be
addressed via selective, late-stage sp3C—H
bond functionalization mediated by P450 catalysts with tailored
site-selectivity. Taking advantage of our recently introduced tools for
high-throughput P450 fingerprinting and fingerprint-driven P450 reactivity
prediction, we evolved P450 variants useful for carrying out the highly
regioselective hydroxylation of two aliphatic sites (C9and C14) in parthenolide
carbocyclic backbone. By chemoenzymatic synthesis, a panel of novel C9- and
C14-modified parthenolide analogs were generated in order to gain initial
structure-activity insights on these previously inaccessible sites of the
molecule. Notably, some of these compounds were found to possess significantly
improved antileukemic potency against primary acute myeloid leukemia cells,
while exhibiting low toxicity against normal mature and progenitor hematopoietic
cells. By identifying two ‘hot spots’ for improving the anticancer
properties of parthenolide, this study highlights the potential of P450-mediated
C—H functionalization as an enabling, new strategy for the late stage
manipulation of bioactive natural product scaffolds.
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