Molecular mechanisms of apoptosis induction in chronic lymphocytic leukemia

CLL is the most common adult leukemia in the Western World, yet very little is known about the biology of this disease. CLL cells have very high levels of NF-κB activity. Factors such as CD40 ligation and phorbol ester treatment induce NF-κB activity and also prevent apoptosis. Previous data from our laboratory demonstrated that MG-132, a proteasome inhibitor, blocked NF-κB activation and promoted apoptosis in CLL cells. These data suggested to us that NF-κB mediates survival in CLL. We examined NF-κB activity using two different chemotherapeutic agents, PS-341 and arsenic trioxide. PS-341, a proteasome inhibitor blocked NF-κB in CLL cells. This however, did not correlate with cell death. Resistant patient isolates displayed delayed Smac/DIABLO release in comparison to cytochrome c release. This suggests that IAPs are contributing to CLL cell survival and drug-resistance. Arsenic trioxide did not block NF-κB activity at therapeutic doses. However it was a potent inducer of apoptosis in CLL cells. We identified a novel mechanism by which arsenic induces increases in mitochondrial calcium to induce cytochrome c release and initiate apoptosis. Both PS-341 and arsenic trioxide are currently in Phase II clinical trials at M.D. Anderson Cancer Center. We conclude that NF-κB is not critical for PS-341 or arsenic trioxide-mediated cell death. ^

PROSTATE CANCER STEM CELLS: DRUG TOLERANCE, EXPERIMENTAL RECONSTITUTION AND CASTRATION RESISTANCE

Prostate cancer (PCa) is one of the leading malignancies affecting men in the Western world. Although tremendous effort has been made towards understanding PCa development and developing clinical treatments in the past decades, the exact mechanisms of PCa are still not clearly understood. Emerging evidence has postulated that a population of stem cell-like cells inside a tumor, termed ‘cancer stem cells (CSCs)’, may be the cells responsible for tumor initiation, progression, recurrence, metastasis and therapy resistance. Like CSC studies in other cancer types, it has been reported that PCa also contains CSCs. However, there remain several unresolved questions that need to be clarified. First, the relationship between prostate CSCs (PCSCs) and therapy resistance (chemo- and radio-) is not known. Herein, we have found that not all CSCs are drug-tolerant, and not all drug-tolerant cells are CSCs. Second, whether primary human PCa (HPCa) actually contain PCSCs remains unclear, due to the well-known fact that we have yet to establish a reliable assay system that can reproducibly and faithfully reconstitute tumor regeneration from single HPCa cells. Herein, after utilizing more than 114 HPCa samples we have provided evidence that immortalized bone marrow-derived stromal cells (Hs5) can help dissociated HPCa cells generate undifferentiated tumors in immunodeficient NOD/SCID-IL2Rγ-/- mice, and the undifferentiated PCa cells seem to have a survival advantage to generate tumors. Third, the evolution of PCa from androgen dependent to the lethally castration resistant (CRPC) stage remains enigmatic, and the cells responsible for CRPC development have not been identified. Herein, we have found a putative cell population, ALDH+CD44+α2β1+ PCa cells that may represent a cell-of-origin for CRPC. Taken together, our work has improved our understanding of PCSC properties, possibly highlighting a potential therapeutic target for CRPC.

Nature and community in Western culture: Wendell Berry's alternative tradition

This dissertation is an examination of the ideals and practices that have characterized Western culture's relationship to the natural world. The conventional approach, depicted by some of the most prominent ecological publications of recent years, criticizes the Western tradition for both its ideals and practices. The ideals are assumed to be best represented in Western philosophy and religion and both of these sources have been indicted. These ideals are coupled with the Western way of life that is equally indicted as exploitive and destructive. Author, professor and farmer, Wendell Berry, offers an alternative to these indictments. Berry insists that a theme, advocating ecological accountability, runs through some of the West's most significant literature and that Western tradition contains a practice that can support these ecological principles. ^