Mitochondrial apoptosis and BH3 mimetics

Sun

Cell Biology International

et al. 2017

Parkinson's disease (PD) is a progressive neurodegenerative disease, leading to tremor, rigidity, bradykinesia, and gait impairment. Salidroside has been reported to exhibit antioxidative and neuroprotective properties in PD. However, the underlying neuroprotective mechanisms effects of salidroside are poorly understood. Recently, a growing body of evidences suggest that silent information regulator 1 (SIRT1) plays important roles in the pathophysiology of PD. Hence, the present study investigated the roles of SIRT1 in neuroprotective effect of salidroside against N-methyl-4-phenylpyridinium (MPP þ )-induced SH-SY5Y cell injury. Our findings revealed that salidroside attenuates MPP þ -induced neurotoxicity as evidenced by the increase in cell viability, and the decreases in the caspase-3 activity and apoptosis ratio. Simultaneously, salidroside pretreatment remarkably increased SIRT1 activity, SIRT1 mRNA and protein levels in MPP þ -treated SH-SY5Y cell. However, sirtinol, a SIRT1 activation inhibitor, significantly blocked the inhibitory effects of salidroside on MPP þ -induced cytotoxicity and apoptosis. In addition, salidroside abolished MPP þ -induced the production of reactive oxygen species (ROS), the upregulation of NADPH oxidase 2 (NOX2) expression, the down-regulations of superoxide dismutase (SOD) activity and glutathione (GSH) level in SH-SY5Y cells, while these effects were also blocked by sirtinol. Finally, we found that the inhibition of salidroside on MPP þ -induced phosphorylation of p38, extracellular signal-regulated kinase (ERK) and c-Jun NH2-terminal kinase (JNK) were also reversed by sirtinol in SH-SY5Y cells. Taken together, these results indicated that SIRT1 contributes to the neuroprotection of salidroside against MPP þ -induced apoptosis and oxidative stress, in part through suppressing of mitogen-activated protein kinase (MAPK) pathways.

Section: Resultsmentioning

confidence: 99%

SIRT1 mediates salidroside‐elicited protective effects against MPP⁺‐induced apoptosis and oxidative stress in SH‐SY5Y cells: involvement in suppressing MAPK pathways

Sun

Cell Biology International

et al. 2017

Journal of Leukocyte Biology

“…Direct and specific inhibitors against Mcl‐1 are so far lacking. The progress in the search of small compounds, selective against Mcl‐1, is summarized in recently published reports . Mcl‐1 plays a central role in chemoresistance to anti‐tubulin agents as vincristine.…”

Section: Targeting Mitochondria In Therapy Of T‐allmentioning

confidence: 99%

Mitochondria as emerging targets for therapies against T cell acute lymphoblastic leukemia

Olivas-Aguirre

Pottosin

Dobrovinskaya

2019

Acute lymphoblastic leukemia (ALL) comprises a heterogeneous group of hematologic malignancies, arising from diverse genetic alterations in the early lymphocyte development. T‐cell subtype of ALL (T‐ALL) accounts for about 15% and 25% of ALL in children and adults, respectively. Being less frequent among ALL subtypes, T‐ALL represents a high‐risk factor for poor prognosis due to its aggressiveness and resistance to common antileukemic drugs. Mitochondria were widely explored recently as a target for anticancer treatment because they are involved in a metabolic reprogramming of a cancer cell and play key roles in reactive oxygen species generation, Ca2+ signaling, and cell death induction. Accordingly, a new class of anticancer compounds named mitocans has been developed, which target mitochondria at distinct crucial points to promote their dysfunction and subsequent cell death. The present review analyses the role of mitochondria in malignant reprogramming and emerging therapeutic strategies targeting mitochondria as an “Achilles’ heel” in T‐ALL, with an emphasis on BH3 mimetics, sequestering pro‐survival BCL proteins and voltage‐dependent anion channel (VDAC)1‐directed drugs, which promote the suppression of aerobic glycolysis, VDAC1 closure, mitochondrial Ca2+ overload, stoppage of the oxidative phosphorylation, oxidative stress, and release of proapoptotic factors.

“…And we believe that Caspase-3 participates in the cordycepin induced apoptosis in CCA. Moreover, the Bcl-2 family is the key mediator of the intrinsic (mitochondrial) pathway, which includes some of the most extensive-studied proteins, such as Bcl-2, the antiapoptotic protein, Bax, the pro-apoptotic protein [22]. The ratio of Bcl-2/Bax is usually used to assess the occurrence of apoptosis.…”

Section: Discussionmentioning

confidence: 99%

Cordycepin inhibits cell growth and induces apoptosis in human cholangiocarcinoma

Wang¹,

Mao²,

Wang³

et al. 2017

neo

The purpose of this study was to explore the role of cordycepin in human cholangiocarcinoma (CCA) cell growth and apoptosis. In the present study, colony formation assay, cell-counting kit-8 (CCK-8) assay and tumor xenograft experiment were performed to evaluate the effect of cordycepin on human CCA cell growth in vitro and in vivo; flow cytometric analysis was performed to evaluate the effect of cordycepin on cell apoptosis; quantitative real-time reverse transcription PCR (qRT-PCR) and western blot assays were performed to evaluate the expression levels of Caspase-3, Bcl-2 and Bax. The results showed that cordycepin inhibited cell growth in QBC939 and RBE cells in vitro and it could also inhibit QBC939 cells growth in vivo. Furthermore, the flow cytometric analysis, qRT-PCR and western blot assays showed that cordycepin could trigger QBC939 and RBE cells apoptosis by regulating the expression levels of Caspase-3, Bcl-2 and Bax. And we proposed that cordycepin could inhibit human CCA cell growth in vitro and in vivo, while, this function is related to the induction of cell apoptosis.