Hematopoietic stem cells (HSCs) are a rare population of somatic stem cells that maintain blood production and are uniquely wired to adapt to diverse cellular fates during the lifetime of an organism. Recent studies have highlighted a central role for metabolic plasticity in facilitating cell fate transitions and in preserving HSC functionality and survival. This review summarizes our current understanding of the metabolic programs associated with HSC quiescence, self-renewal and lineage commitment and highlights the mechanistic underpinnings of these changing bioenergetics’ programs. It also discusses the therapeutic potential of targeting metabolic drivers in the context of blood malignancies.

Glioblastoma (GBM) is a high-grade central nervous system malignancy and despite aggressive treatment strategies, GBM patients have a median survival time of just 1 year. Chloroquine (CQ), an antimalarial lysosomotropic agent, has been identified as a potential adjuvant in the treatment regimen of GBMs. However, the mechanism of CQ-induced tumor cell death is poorly defined. We and others have shown that CQ-mediated cell death may be p53-dependent and at least in part due to the intrinsic apoptotic death pathway. Here, we investigated the effects of CQ on 5 established human GBM lines, differing in their p53 gene status. CQ was found to induce a concentration-dependent death in each of these cell lines. Although CQ treatment increased caspase-3-like enzymatic activity in all 5 cell lines, a broad-spectrum caspase inhibitor did not significantly attenuate death. Moreover, CQ caused an accumulation of autophagic vacuoles in all cell lines and was found to affect the levels and subcellular distribution of cathepsin D, suggesting that altered lysosomal function may also play a role in CQ-induced cell death. Thus, CQ can induce p53-independent death in gliomas that do not require caspase-mediated apoptosis. To potentially identify more potent chemotherapeutics, various CQ derivatives and lysosomotropic compounds were tested on the GBM cells. Quinacrine and mefloquine were found to be more potent than CQ in killing GBM cells in vitro and given their superior blood-brain barrier penetration compared with CQ may prove more efficacious as chemotherapeutic agents for GBM patients.

The role of autophagy, traditionally considered a cellular homeostatic and recycling mechanism, has expanded dramatically to include an involvement in discrete stages of tumor initiation and development. Gliomas are the most aggressive and also the most common brain malignancies. Current treatment modalities have only a modest effect on patient outcomes. Resistance to apoptosis, a hallmark of most cancers, has driven the search for novel targets in cancer therapy. The autophagy lysosomal pathway is one such target that is being explored in multiple cancers including gliomas and is a promising avenue for further therapeutic development. This review summarizes our current understanding of the autophagic process and its potential utility as a target for glioma therapy.

Tamoxifen is widely used to treat estrogen receptor (ER)-positive breast cancer. Recent findings that tamoxifen and its derivative 4-dehydroxy-tamoxifen (OHT) can exert ER-independent cytotoxic effects have prompted the initiation of clinical trials to evaluate its use in ER-negative malignancies. For example, tamoxifen and OHT exert cytotoxic effects in malignant peripheral nerve sheath tumors (MPNSTs) where estrogen is not involved. In this study, we gained insights into the ER-independent cytotoxic effects of OHT by studying how it kills MPNST cells. Although caspases were activated following OHT treatment, caspase inhibition provided no protection from OHT-induced death. Rather, OHT-induced death in MPNST cells was associated with autophagic induction and attenuated by genetic inhibition of autophagic vacuole formation. Mechanistic investigations revealed that OHT stimulated K-Ras degradation through autophagy induction, which is critical for survival of MPNST cells. Similarly, we found that OHT induced K-Ras degradation in breast, colon, glioma and pancreatic cancer cells. Our findings describe a novel mechanism of autophagic death triggered by tamoxifen and OHT in tumor cells that may be more broadly useful clinically in cancer treatment.