Primary effusion lymphoma (PEL) is a rare B-cell neoplasm, associated with Kaposi sarcoma-associated herpes virus/human herpes virus-8 (KSHV/HHV-8), arising as malignant effusions in body cavities. PEL cells do not harbor conventional genetic cancer mutations; however, their oncogenesis is mainly attributed to HHV-8 latent genes. Treatment strategies are inefficient resulting in poor prognosis of PEL patients, stressing the need for new effective therapy. ST1926 is a synthetic retinoid with favorable antitumor properties and no cross-resistance with the natural retinoid, all-trans retinoic acid. ST1926 has shown potent apoptotic activities on a variety of solid tumors and hematologic malignancies in in vitro and in vivo models. In the present study we elucidated the antitumor activities and underlying molecular mechanism of ST1926 using in vitro, ex vivo, and in vivo PEL preclinical models. ST1926, at sub‑micromolar concentrations, displayed potent antiproliferative effects on PEL cell lines and malignant ascites. Furthermore, ST1926 treatment of PEL cells and ascites resulted in their accumulation in the sub-G1 region, S phase cell cycle arrest, early DNA damage, PARP cleavage and p53 activation including the upregulation of its target genes p21 and Bax. However, ST1926 did not significantly modulate HHV-8 latent viral transcripts. Importantly, ST1926 delayed formation of ascites and enhanced survival of PEL mice. These results highlight the therapeutic potential of ST1926 in combination with drugs that target HHV-8 in PEL patients.
Amiodarone (AMD) is an antiarrhythmic drug that induces idiosyncratic toxicity. Environmental pollutants, including heavy metals, could interact with its toxicity by affecting pharmacokinetics and pharmacodynamics. Other levels of interaction could exist in yeast, such as oxidative stress and the general stress response. In this study, we investigated the interaction of mercury chloride (HgCl2) and cadmium chloride (CdCl2) with AMD toxicity on Saccharomyces cerevisiae. Interaction type - synergistic, additive, or antagonistic - was determined by median drug effect analysis using “CompuSyn”. HgCl2 potentiated AMD toxicity at high doses (≥ 71.4 μm, which yielded more than 60% inhibition). CdCl2 acted similarly at high doses (≥ 57.9 μm). An antagonistic effect appeared at lower doses with both heavy metals (≤ 49.4 μm for HgCl2 and AMD; ≤ 18.9 μm for CdCl2 and AMD). The threshold concentrations (HgCl2 or CdCl2 combined with AMD) that switched the interaction from antagonistic to additive, and then to synergistic, were decreased in the yeast strain mutant in catalase ( CTT1), suggesting an important role for this enzyme. Moreover, mutation of the nutrient sensing receptor gene GPR1 caused the synergistic interaction of CdCl2, but not HgCl2, with AMD to occur at the lowest tested concentrations (1.2 μm). The reverse was obtained with the mutant strain in calcium–manganese transporter gene PMR1, where the synergistic interaction of HgCl2 with AMD occurred at concentrations (20.7 μm) lower than that of the wild type (71.4 μm). These results demonstrated a dose-dependent interaction between the two heavy metals with AMD toxicity, and the involvement of oxidative stress, calcium homeostasis, and nutrient sensing in the observed interaction.
Amiodarone (AMD) is an antiarrhythmic drug prescribed to treat ventricular tachycardia and fibrillation. However, it causes an unpredictable toxicity (idiosyncratic), which may depend on co‐exposure to pollutants. AMD toxicity involves calcium homeostasis alteration and oxidative stress, which are also affected by cigarette smoke (CS). We investigated the interaction of CS‐condensate (CSC), phenanthrene, and benzo(a)pyrene with AMD toxicity on Saccharomyces cerevisiae. AMD toxicity was reduced by CSC or phenanthrene. Benzo(a)pyrene mildly decreased AMD toxicity on the wild‐type strain, but not on the catalase‐CTT1 mutant. This latter and other mutants in glucose receptor‐GPR1 or calcium transporter‐PMR1 showed lower antagonistic effect to AMD by CSC or phenanthrene relative to the wild type, suggesting roles of oxidative stress, calcium homeostasis, and hexose‐sensing in this interaction.
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