All-trans retinoic acid (tRA) and arsenic trioxide (As 2 O 3 ) induce non-cross-resistant complete clinical remission in patients with acute promyelocytic leukemia with t(15;17) translocation and target PML-RAR␣, the leukemogenic protein, by different pathways suggesting a possible therapeutic synergism. To evaluate this possibility, this study examined the effect of As 2 O 3 on tRA-induced differentiation and, conversely, the effect of tRA on As 2 O 3 -induced apoptosis. As 2 O 3 at subapoptotic concentrations (0.5 M) decreased tRA-induced differentiation in NB4 cells but synergized with atRA to induce differentiation in tRA-resistant NB4 subclones MR-2 and R4 cells as measured by nitroblue tetrazolium reduction and tRA-inducible genes (TTGII, RAR␤, RIG-E). tRA cleaved PML-RAR␣ into distinct fragments in NB4 but not in tRAresistant MR-2 or R4 cells, whereas As 2 O 3 completely degraded PML-RAR␣ in all 3 cell lines. As 2 O 3 -induced apoptosis was decreased by tRA pretreatment of NB4 cells but not of R4 cells and was associated with a strong induction of Bfl-1/A1 expression, a Bcl-2 protein family member. Severe combined immunodeficient mice bearing NB4 cells showed an additive survival effect after sequential treatment, but a toxic effect was observed after simultaneous treatment with tRA and As 2 O 3 . These data suggest that combined As 2 O 3 and tRA treatment may be more effective than single agents in tRAresistant patients. Although in vitro data do not always translate to in vivo response, toxicity and potential drug antagonism may be diminished by decreasing the concentration of As 2 O 3 when given at the same time with therapeutic levels of tRA. IntroductionAcute promyelocytic leukemia (APL) is a specific type of acute myeloid leukemia characterized by the t(15;17) translocation that fuses the PML gene on chromosome 15 to the retinoic acid receptor ␣ (RAR␣) gene on chromosome 17 to form the fusion gene and leukemogenic protein PML-RAR␣. 1,2 The specific sensitivity of APL cells to all-trans retinoic acid (tRA)-induced differentiation has been exploited to achieve a 90% remission rate with a projected 60% to 70% cure of patients with APL when combined with chemotherapy. [3][4][5][6][7] However, the disease may relapse with resistance to further tRA and chemotherapy treatment. 8 The recent discovery that treatment with As 2 O 3 induces durable remission in APL patients in relapse after tRA or chemotherapy has provided a novel therapy for APL patients. 9-11 However, the reported chronic toxicities and carcinogenicity of As 2 O 3 has hampered its acceptance as a first-choice drug, 12 even though limited side effects were found in relapsed APL patients successfully treated with As 2 O 3 . 10,11 Consideration of the facts that the toxicity of As 2 O 3 is dose dependent and reversible and that small amounts of As 2 O 3 have been used in traditional Chinese medicine suggests that it may be possible to use As 2 O 3 as a first-choice drug if low concentrations prove effective.Arsenic trioxide induces both apoptos...

Acetyl-keto-B-boswellic acid (AKBA), a triterpenoid isolated from Boswellia carterri Birdw and Boswellia serrata, has been found to inhibit tumor cell growth and to induce apoptosis. The apoptotic effects and the mechanisms of action of AKBA were studied in LNCaP and PC-3 human prostate cancer cells. AKBA induced apoptosis in both cell lines at concentrations above 10 Mg/mL. AKBA-induced apoptosis was correlated with the activation of caspase-3 and caspase-8 as well as with poly(ADP)ribose polymerase (PARP) cleavage. The activation of caspase-8 was correlated with increased levels of death receptor (DR) 5 but not of Fas or DR4. AKBA-induced apoptosis, caspase-8 activation, and PARP cleavage were inhibited by knocking down DR5 using a small hairpin RNA. AKBA treatment increased the levels of CAAT/enhancer binding protein homologous protein (CHOP) and activated a DR5 promoter reporter but did not activate a DR5 promoter reporter with the mutant CHOP binding site. These results suggest that AKBA induces apoptosis in prostate cancer cells through a DR5-mediated pathway, which probably involves the induced expression of CHOP.

Key Points• LCN2 acts to generate reactive oxygen species, leading to increased DNA strand breaks and apoptosis in normal CD34 1 cells.• LCN2 promotes the generation of osteoblasts but diminishes adipogenesis, resembling the composition of the MF marrow microenvironment.Myelofibrosis (MF) is characterized by cytopenias, constitutional symptoms, splenomegaly, and marrow histopathological abnormalities (fibrosis, increased microvessel density, and osteosclerosis). The microenvironmental abnormalities are likely a consequence of the elaboration of a variety of inflammatory cytokines generated by malignant megakaryocytes and monocytes. We observed that levels of a specific inflammatory cytokine, lipocalin-2 (LCN2), were elevated in the plasmas of patients with myeloproliferative neoplasms (MF > polycythemia vera or essential thrombocythemia) and that LCN2 was elaborated by MF myeloid cells. LCN2 generates increased reactive oxygen species, leading to increased DNA strand breaks and apoptosis of normal, but not MF, CD34 1 cells. Furthermore, incubation of marrow adherent cells or mesenchymal stem cells with LCN2 increased the generation of osteoblasts and fibroblasts, but not adipocytes. LCN2 priming of mesenchymal stem cells resulted in the upregulation of RUNX2 gene as well as other genes that are capable of further affecting osteoblastogenesis, angiogenesis, and the deposition of matrix proteins. These data indicate that LCN2 is an additional MF inflammatory cytokine that likely contributes to the creation of a cascade of events that results in not only a predominance of the MF clone but also a dysfunctional microenvironment. (Blood. 2015;126(8):972-982)