Translational assessment of mitochondrial dysfunction of pancreatic cancer from in vitro gene microarray and animal efficacy studies, to early clinical studies, via the novel tumor-specific anti-mitochondrial agent, CPI-613.

Study Rationale And Objectives: Via genetic alterations, malignant transformation and proliferation are associated with extensive alterations of mitochondrial energy metabolism of tumor cells. Thus, inhibition of the altered form of mitochondrial energy metabolism of tumor cells may be an effective therapy for cancers. This study performed translational assessment of mitochondrial dysfunction of pancreatic cancer from in vitro gene microarray and animal efficacy studies, to early clinical studies, via the novel tumor-specific anti-mitochondrial agent, CPI-613.

A phase I study of the first-in-class antimitochondrial metabolism agent, CPI-613, in patients with advanced hematologic malignancies.

Purpose: The lipoate derivative CPI-613 is a first-in-class agent that targets mitochondrial metabolism. This study determined the effects of CPI-613 on mitochondrial function and defined the MTD, pharmacokinetics, and safety in patients with relapsed or refractory hematologic malignancies.

Experimental Design: Human leukemia cell lines were exposed to CPI-613 and mitochondrial function was assayed.

Multi-faced neuroprotective effects of Ginsenoside Rg1 in an Alzheimer mouse model.

There has been no extensive characterization of the effects of Ginsenoside Rg1, a pharmacological active component purified from the nature product ginseng, in an Alzheimer's disease mouse model. The well-characterized transgenic Alzheimer disease (AD) mice over expressing amyloid precursor protein (APP)/Aβ (Tg mAPP) and nontransgenic (nonTg) littermates at age of 6 and 9 months were treated with Rg 1 for three months via intraperitoneal injection. Mice were then evaluated for changes in amyloid pathology, neuropathology and behavior.

RAGE-dependent signaling in microglia contributes to neuroinflammation, Abeta accumulation, and impaired learning/memory in a mouse model of Alzheimer's disease.

Microglia are critical for amyloid-beta peptide (Abeta)-mediated neuronal perturbation relevant to Alzheimer's disease (AD) pathogenesis. We demonstrate that overexpression of receptor for advanced glycation end products (RAGE) in imbroglio exaggerates neuroinflammation, as evidenced by increased proinflammatory mediator production, Abeta accumulation, impaired learning/memory, and neurotoxicity in an Abeta-rich environment. Transgenic (Tg) mice expressing human mutant APP (mAPP) in neurons and RAGE in microglia displayed enhanced IL-1beta and TNF-alpha production, increased infiltration of microglia and astrocytes, accumulation of Abeta, reduced acetylcholine esterase (AChE) activity, and accelerated deterioration of spatial learning/memory.

ABAD enhances Abeta-induced cell stress via mitochondrial dysfunction.

Amyloid-beta peptide (Abeta) binding alcohol dehydrogenase (ABAD), an enzyme present in neuronal mitochondria, is a cofactor facilitating Abeta-induced cell stress. We hypothesized that ABAD provides a direct link between Abeta and cytotoxicity via mitochondrial oxidant stress. Neurons cultured from transgenic (Tg) mice with targeted overexpression of a mutant form of amyloid precursor protein and ABAD (Tg mAPP/ABAD) displayed spontaneous generation of hydrogen peroxide and superoxide anion, and decreased ATP, as well as subsequent release of cytochrome c from mitochondria and induction of caspase-3-like activity followed by DNA fragmentation and loss of cell viability.

RAGE potentiates Abeta-induced perturbation of neuronal function in transgenic mice.

Receptor for Advanced Glycation Endproducts (RAGE), a multiligand receptor in the immunoglobulin superfamily, functions as a signal-transducing cell surface acceptor for amyloid-beta peptide (Abeta). In view of increased neuronal expression of RAGE in Alzheimer's disease, a murine model was developed to assess the impact of RAGE in an Abeta-rich environment, employing transgenics (Tgs) with targeted neuronal overexpression of RAGE and mutant amyloid precursor protein (APP). Double Tgs (mutant APP (mAPP)/RAGE) displayed early abnormalities in spatial learning/memory, accompanied by altered activation of markers of synaptic plasticity and exaggerated neuropathologic findings, before such changes were found in mAPP mice.