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Protein phosphatase 2A (PP2A), a heterotrimeric holoenzyme (scaffolding, catalytic, and regulatory subunits), regulates dephosphorylation for more than half of serine/threonine phosphosites and exhibits diverse cellular functions. Although several studies on natural products and miRNAs have emphasized their impacts on PP2A regulation, their connections lack systemic organization. Moreover, only part of the PP2A family has been investigated. This review focuses on the PP2A‐modulating effects of natural products and miRNAs' interactions with potential PP2A targets in cancer and non‐cancer cells. PP2A‐modulating natural products and miRNAs were retrieved through a literature search. Utilizing the miRDB database, potential PP2A targets of these PP2A‐modulating miRNAs for the whole set (17 members) of the PP2A family were retrieved. Finally, PP2A‐modulating natural products and miRNAs were linked via a literature search. This review provides systemic directions for assessing natural products and miRNAs relating to the PP2A‐modulating functions in cancer and disease treatments. [ABSTRACT FROM AUTHOR]

Antioral cancer drugs need a greater antiproliferative impact on cancer than on normal cells. Demethoxymurrapanine (DEMU) inhibits proliferation in several cancer cells, but an in‐depth investigation was necessary. This study evaluated the proliferation‐modulating effects of DEMU, focusing on oral cancer and normal cells. DEMU (0, 2, 3, and 4 μg/mL) at 48 h treatments inhibited the proliferation of oral cancer cells (the cell viability (%) for Ca9‐22 cells was 100.0 ± 2.2, 75.4 ± 5.6, 26.0 ± 3.8, and 15.4 ± 1.4, and for CAL 27 cells was 100.0 ± 9.4, 77.2 ± 5.9, 57.4 ± 10.7, and 27.1 ± 1.1) more strongly than that of normal cells (the cell viability (%) for S‐G cells was 100.0 ± 6.6, 91.0 ± 4.6, 95.0 ± 2.6, and 95.8 ± 5.5), although this was blocked by the antioxidant N‐acetylcysteine. The presence of oxidative stress was evidenced by the increase of reactive oxygen species and mitochondrial superoxide and the downregulation of the cellular antioxidant glutathione in oral cancer cells, but these changes were minor in normal cells. DEMU also caused greater induction of the subG1 phase, extrinsic and intrinsic apoptosis (annexin V and caspases 3, 8, and 9), and DNA damage (γH2AX and 8‐hydroxy‐2‐deoxyguanosine) in oral cancer than in normal cells. N‐acetylcysteine attenuated all these DEMU‐induced changes. Together, these data demonstrate the preferential antiproliferative function of DEMU in oral cancer cells, with the preferential induction of oxidative stress, apoptosis, and DNA damage in these cancer cells, and low cytotoxicity toward normal cells. [ABSTRACT FROM AUTHOR]

Increased neddylation benefits the survival of several types of cancer cells. The inhibition of neddylation has the potential to exert anticancer effects but is rarely assessed in oral cancer cells. This study aimed to investigate the antiproliferation potential of a neddylation inhibitor MLN4924 (pevonedistat) for oral cancer cells. MLN4924 inhibited the cell viability of oral cancer cells more than that of normal oral cells (HGF‐1) with 100% viability, that is, IC50 values of oral cancer cells (CAL 27, OC‐2, and Ca9‐22) are 1.8, 1.4, and 1.9 μM. MLN4924 caused apoptotic changes such as the subG1 accumulation, activation of annexin V, pancaspase, and caspases 3/8/9 of oral cancer cells at a greater rate than in normal oral cells. MLN4924 induced greater oxidative stress in oral cancer cells compared to normal cells by upregulating reactive oxygen species and mitochondrial superoxide and depleting the mitochondrial membrane potential and glutathione. In oral cancer cells, preferential inductions also occurred for DNA damage (γH2AX and 8‐oxo‐2′‐deoxyguanosine). Therefore, this investigation demonstrates that MLN4924 is a potential anti‐oral‐cancer agent showing preferential inhibition of apoptosis and promotion of DNA damage with fewer cytotoxic effects on normal cells. [ABSTRACT FROM AUTHOR]

The antibiotic antimycin A (AMA) is commonly used as an inhibitor for the electron transport chain but its application in anticancer studies is rare. Recently, the repurposing use of AMA in antiproliferation of several cancer cell types has been reported. However, it is rarely investigated in oral cancer cells. The purpose of this study is to investigate the selective antiproliferation ability of AMA treatment on oral cancer cells. Cell viability, flow cytometry, and western blotting were applied to explore its possible anticancer mechanism in terms of both concentration‐ and exposure time‐effects. AMA shows the higher antiproliferation to two oral cancer CAL 27 and Ca9‐22 cell lines than normal oral HGF‐1 cell lines. Moreover, AMA induces the production of higher reactive oxygen species (ROS) levels and pan‐caspase activation in oral cancer CAL 27 and Ca9‐22 cells than in normal oral HGF‐1 cells, providing the possible mechanism for its selective antiproliferation effect of AMA. In addition to ROS, AMA induces mitochondrial superoxide (MitoSOX) generation and depletes mitochondrial membrane potential (MitoMP). This further supports the AMA‐induced oxidative stress changes in oral cancer CAL 27 and Ca9‐22 cells. AMA also shows high expressions of annexin V in CAL 27 and Ca9‐22 cells and cleaved forms of poly (ADP‐ribose) polymerase (PARP), caspase 9, and caspase 3 in CAL 27 cells, supporting the apoptosis‐inducing ability of AMA. Furthermore, AMA induces DNA damage (γH2AX and 8‐oxo‐2′‐deoxyguanosine [8‐oxodG]) in CAL 27 and Ca9‐22 cells. Notably, the AMA‐induced selective antiproliferation, oxidative stress, and DNA damage were partly prevented from N‐acetylcysteine (NAC) pretreatments. Taken together, AMA selectively kills oral cancer cells in an oxidative stress‐dependent mechanism involving apoptosis and DNA damage. [ABSTRACT FROM AUTHOR]

Discovering drug candidates for the modulation of metastasis is of great importance in inhibiting oral cancer malignancy. Although most pomegranate extract applications aim at the antiproliferation of cancer cells, its antimetastatic effects remain unclear, especially for oral cancer cells. The aim of this study is to evaluate the change of two main metastasis characters, migration and invasion of oral cancer cells. Further, we want to explore the molecular mechanisms of action of pomegranate extract (POMx) at low cytotoxic concentration. We found that POMx ranged from 0 to 50 μg/mL showing low cytotoxicity to oral cancer cells. In the case of oral cancer HSC‐3 and Ca9‐22 cells, POMx inhibits wound healing migration, transwell migration, and matrix gel invasion. Mechanistically, POMx downregulates matrix metalloproteinase (MMP)‐2 and MMP‐9 activities and expressions as well as epithelial‐mesenchymal transition (EMT) signaling. POMx upregulates extracellular signal‐regulated kinases 1/2 (ERK1/2), but not c‐Jun N‐terminal kinase (JNK) and p38 expression. Addition of ERK1/2 inhibitor (PD98059) significantly recovered the POMx‐suppressed transwell migration and MMP‐2/−9 activities in HSC‐3 cells. Taken together, these findings suggest to further test low cytotoxic concentrations of POMx as a potential antimetastatic therapy against oral cancer cells. [ABSTRACT FROM AUTHOR]

LY303511 was developed as a negative control of LY294002 without pan‐phosphoinositide 3‐kinase (PI3K) inhibition. We hypothesize LY303511 generate reactive oxygen species (ROS) to induce apoptosis for killing oral cancer cells. In MTS assay, LY303511 dose‐responsively decreases survival in three kinds of oral cancer cells but little damage to normal oral cells (HGF‐1). Two oral cancer cells (CAL 27 and SCC‐9) with highly sensitivity to LY303511 were used. In 7‐aminoactinomycin D (7AAD) assay, LY303511 slightly increases subG1 population in oral cancer cells. In annexin V/7AAD and/or pancaspase assays, LY303511 induces apoptosis in oral cancer cells but HGF‐1 cells remains in basal level. In oxidative stress, LY303511 induces ROS and mitochondrial superoxide in oral cancer cells. In 8‐oxo‐2'‐deoxyguanosine assay, LY303511 induces oxidative DNA damage in oral cancer cells. In zebrafish model, LY303511 inhibits CAL 27‐xenografted tumor growth. Therefore, LY303511 displays antiproliferation potential against oral cancer cells in vitro and in vivo. [ABSTRACT FROM AUTHOR]

Nepenthes plants are regarded as a kind of Traditional Chinese Medicine for several diseases but its anticancer activity remain unclear. The subject of this study is to evaluate the antiproliferation effects on oral cancer cells by Nepenthes plants using ethyl acetate extract of Nepenthes adrianii x clipeata (EANA). Cell viability was detected using MTS assay. Its detailed mechanisms including cell cycle, apoptosis, oxidative stress, and DNA damage were explored by flow cytometry or western blotting. For 24 hours EANA treatment, five kinds of oral cancer cells (CAL 27, Ca9‐22, OECM‐1, HSC‐3, and SCC9) show IC50 values of cell viability ranging from 8 to 17 μg/mL but the viability of normal oral cells (HGF‐1) remains over 80%. Subsequently, CAL 27 and Ca9‐22 cells with high sensitivity to EANA were chosen to investigate the detailed mechanism. EANA displays the time course and concentration effects for inducing apoptosis based on flow cytometry (subG1 and annexin V analyses) and western blotting [cleaved poly (ADP‐ribose) polymerase (c‐PARP)]. Oxidative stress and DNA damage were induced by EANA treatments in oral cancer cells through reactive oxygen species (ROS), mitochondrial membrane potential disruption, mitochondrial superoxide, and γH2AX. All these changes of EANA treatments in oral cancer cells were reverted by the ROS scavenger N‐acetylcysteine pretreatment. Therefore, EANA induces preferential killing, apoptosis, and DNA damage against oral cancer cells through oxidative stress. [ABSTRACT FROM AUTHOR]

Several functionalized chromones, the key components of naturally occurring oxygenated heterocycles, have anticancer effects but their sulfone compounds are rarely investigated. In this study, we installed a sulfonyl substituent to chromen‐4‐one skeleton and synthesized CHW09 to evaluate its antioral cancer effect in terms of cell viability, cell cycle, apoptosis, oxidative stress, and DNA damage. In cell viability assay, CHW09 preferentially kills two oral cancer cells (Ca9‐22 and CAL 27), less affecting normal oral cells (HGF‐1). Although CHW09 does not change the cell cycle distribution significantly, CHW09 induces apoptosis validated by flow cytometry for annexin V and by western blotting for cleaved poly(ADP‐ribose) polymerase (PARP), and caspases 3/8/9. These apoptosis signaling expressions are partly decreased by apoptosis inhibitor (Z‐VAD‐FMK) or free radical scavenger (N‐acetylcysteine). Furthermore, CHW09 induces oxidative stress validated by flow cytometry for the generations of reactive oxygen species (ROS) and mitochondrial superoxide (MitoSOX), and the suppression of mitochondrial membrane potential (MMP). CHW09 also induces DNA damage validated by flow cytometry for the increases of DNA double strand break marker γH2AX and oxidative DNA damage marker 8‐oxo‐2′‐deoxyguanosine (8‐oxodG). Therefore, our newly synthesized CHW09 induces apoptosis, oxidative stress, and DNA damage, which may lead to preferential killing of oral cancer cells compared with normal oral cells. [ABSTRACT FROM AUTHOR]

Currently, chemotherapy or chemotherapy combination radiotherapy is used for metastatic UTUC patients, and adjuvant therapy for locally advanced UTUC is used after RNU. Limited research has been carried out of local UTUC patients who are unsuitable for operation using chemotherapy or chemotherapy combination radiotherapy. A total of 13 patients were diagnosed as having a high-grade tumor using the World Health Organization grading system.[5] Nine patients had tumors in the renal pelvis and seven had tumors in the ureter. [Extracted from the article]

Abstract: Reactive oxygen species (ROS) induction had been previously reported in 4β‐hydroxywithanolide (4βHWE)‐induced selective killing of oral cancer cells, but the mechanism involving ROS and the DNA damage effect remain unclear. This study explores the role of ROS and oxidative DNA damage of 4βHWE in the selective killing of oral cancer cells. Changes in cell viability, morphology, ROS, DNA double strand break (DSB) signaling (γH2AX foci in immunofluorescence and DSB signaling in western blotting), and oxidative DNA damage (8‐oxo‐2′deoxyguanosine [8‐oxodG]) were detected in 4βHWE‐treated oral cancer (Ca9‐22) and/or normal (HGF‐1) cells. 4βHWE decreased cell viability, changed cell morphology and induced ROS generation in oral cancer cells rather than oral normal cells, which were recovered by a free radical scavenger N‐acetylcysteine (NAC). For immunofluorescence, 4βHWE also accumulated more of the DSB marker, γH2AX foci, in oral cancer cells than in oral normal cells. For western blotting, DSB signaling proteins such as γH2AX and MRN complex (MRE11, RAD50, and NBS1) were overexpressed in 4βHWE‐treated oral cancer cells in different concentrations and treatment time. In the formamidopyrimidine‐DNA glycolyase (Fpg)‐based comet assay and 8‐oxodG‐based flow cytometry, the 8‐oxodG expressions were higher in 4βHWE‐treated oral cancer cells than in oral normal cells. All the 4βHWE‐induced DSB and oxidative DNA damage to oral cancer cells were recovered by NAC pretreatment. Taken together, the 4βHWE selectively induced DSB and oxidative DNA damage for the ROS‐mediated selective killing of oral cancer cells. [ABSTRACT FROM AUTHOR]

Soft corals-derived natural product, sinularin, was antiproliferative against some cancers but its effect and detailed mechanism on oral cancer cells remain unclear. The subject of this study is to examine the antioral cancer effects and underlying detailed mechanisms in terms of cell viability, oxidative stress, cell cycle analysis, and apoptosis analyses. In MTS assay, sinularin dose-responsively decreased cell viability of three oral cancer cells (Ca9-22, HSC-3, and CAL 27) but only little damage to oral normal cells (HGF-1). This cell killing effect was rescued by the antioxidant N-acetylcysteine (NAC) pretreatment. Abnormal cell morphology and induction of reactive oxygen species (ROS) were found in sinularin-treated oral cancer Ca9-22 cells, however, NAC pretreatment also recovered these changes. Sinularin arrested the Ca9-22 cells at G2/M phase and dysregulated the G2/M regulatory proteins such as cdc2 and cyclin B1. Sinularin dose-responsively induced apoptosis on Ca9-22 cells in terms of flow cytometry (annexin V and pancaspase analyses) and western blotting (caspases 3, 8, 9) and poly (ADP-ribose) polymerase (PARP). These apoptotic changes of sinularin-treated Ca9-22 cells were rescued by NAC pretreatment. Taken together, sinularin induces oxidative stress-mediated antiproliferation, G2/M arrest, and apoptosis against oral cancer cells and may be a potential marine drug for antioral cancer therapy. [ABSTRACT FROM AUTHOR]

Accelerated life testing (ALT) is commonly used to obtain reliability information about a product in a timely manner. Several stress loading designs have been proposed and recent research interests have emerged concerning the development of equivalent ALT plans. Step-stress ALT (SSALT) is one of the most commonly used stress loadings because it usually shortens the test duration and reduces the number of required test units. This article considers two fundamental questions when designing a SSALT and provides formal proofs in answer to each. Namely: (1) can a simple SSALT be designed so that it is equivalent to other stress loading designs? (2) when optimizing a multilevel SSALT, does it degenerate to a simple SSALT plan? The answers to both queries, under certain reasonable model assumptions, are shown to be a qualified YES. In addition, we provide an argument to support the rationale of a common practice in designing a SSALT, that is, setting the higher stress level as high as possible in a SSALT plan. © 2012 Wiley Periodicals, Inc. Naval Research Logistics, 2013 [ABSTRACT FROM AUTHOR]

Conventionally, elements of a multiattribute utility model characterizing a decision maker's preferences, such as attribute weights and attribute utilities, are treated as deterministic, which may be unrealistic because assessment of such elements can be imprecise and erroneous, or differ among a group of individuals. Moreover, attempting to make precise assessments can be time consuming and cognitively demanding. We propose to treat such elements as stochastic variables to account for inconsistency and imprecision in such assessments. Under these assumptions, we develop procedures for computing the probability distribution of aggregate utility for an additive multiattribute utility function (MAUF), based on the Edgeworth expansion. When the distributions of aggregate utility for all alternatives in a decision problem are known, stochastic dominance can then be invoked to filter inferior alternatives. We show that, under certain mild conditions, the aggregate utility distribution approaches normality as the number of attributes increases. Thus, only a few terms from the Edgeworth expansion with a standard normal density as the base function will be sufficient for approximating an aggregate utility distribution in practice. Moreover, the mom symmetric the attribute utility distributions, the fewer the attributes to achieve normality. The Edgeworth expansion thus can provide a basis for a computationally viable approach for representing an aggregate utility distribution with imprecisely specified attribute weights and utilities assessments (or differing weights and utilities across individuals). Practical guidelines for using the Edgeworth approximation are given. The proposed methodology is illustrated using a vendor selection problem. [ABSTRACT FROM AUTHOR]

Traditionally, parameters of multiattribute utility models, representing a decision maker's preference judgements, are treated deterministically. This may be unrealistic, because assessment of such parameters is potentially fraught with imprecisions and errors. We thus treat such parameters as stochastic and investigate how their associated imprecision/errors are propagated in an additive multiattribute utility function in terms of the aggregate variance. Both a no information and a rank order case regarding the attribute weights are considered, assuming a uniform distribution over the feasible region of attribute weights constrained by the respective information assumption. In general, as the number of attributes increases, the variance of the aggregate utility in both cases decreases and approaches the same limit, which depends only on the variances as well as the correlations among the single attribute utilities. However, the marginal change in aggregate utility variance decreases rather rapidly and hence decomposition as a variance reduction mechanism is generally useful but becomes relatively ineffective if the number of attributes exceed about 10. Moreover, it was found that utilities which are positively correlated increase the aggregate utility variance, hence every effort should be made to avoid positive correlations between the single attribute utilities. We also provide guidelines for determining under what condition and to what extent a decision maker should decompose to obtain an aggregate utility variance that is smaller than that of holistic assessments. Extensions of the current model and empirical research to support some of our behavioural assumptions are discussed. [ABSTRACT FROM AUTHOR]