Potential Mechanisms Of Interaction Research Articles

Piezoelectric Response to Coherent Longitudinal and Transverse Acoustic Phonons in a Semiconductor Schottky Diode

We study the generation of microwave electronic signals by pumping a (311) GaAs Schottky diode with compressive and shear acoustic phonons, generated by femtosecond optical excitation of an Al _lm transducer and mode conversion at the Al-GaAs interface. They propagate through the substrate and arrive at the Schottky device on the opposite surface, where they induce a microwave electronic signal. The arrival time, amplitude and polarity of the signals depend on the phonon mode. A theoretical analysis is made of the polarity of the experimental signals. This includes the piezoelectric and deformation potential mechanisms of electron-phonon interaction in a Schottky contact and shows that the piezoelectric mechanism is dominant for both transverse and longitudinal modes with frequencies below 250 GHz and 70 GHz respectively.

GAMBARAN INTERAKSI OBAT HIPOGLIKEMIK ORAL (OHO) DENGAN OBAT LAIN PADA PASIEN DIABETES MELITUS (DM) TIPE II DI APOTEK IMPHI PERIODE OKTOBER 2014 SAMPAI MARET 2015

Increasing complications of diabetes mellitus (DM) have tendency to amount of drug use, which can increase the risk of drug interaction. Drug interaction is a situation arising of administrations more than one drug at the same time that effects each drug can be interfere each other and or both are mutually and or undesirable side effect may a rise which could potentially harm and or doesn’t give clinically significant effect. This research aims to determinate the potential interactions and mechanisms of drug interactions and impacts based on the severity of the effect of therapy in patients type II of diabetes mellitus (DM) at Imphi’s Pharmacy in the period October 2014 until March 2015. The research used descriptive evaluative and retrospective method based on recipe sheets. Data analysis have done by screening of drug interaction and using drug interaction from software lexicomp and drug interaction stockley. The results showed that there are 28 recipe sheets (16,37%) from 171 recipe sheets of 110 patients that potentially occur pharmacodynamic mechanism of drug interaction with as many as 36 events (64,29%) as well as the mechanisms of drug interaction based on the severity of the effect of moderate kind of therapy as much as 40 events

CQ synergistically sensitizes human colorectal cancer cells to SN-38/CPT-11 through lysosomal and mitochondrial apoptotic pathway via p53-ROS cross-talk

Autophagy plays a key role in supporting cell survival against chemotherapy-induced apoptosis. In this study, we found the chemotherapy agent SN-38 induced autophagy in colorectal cancer (CRC) cells. However, inhibition of autophagy using a small molecular inhibitor 3-methyladenine (3-MA) and ATG5 siRNA did not increase SN-38-induced cytotoxicity in CRC cells. Notably, another autophagy inhibitor chloroquine (CQ) synergistically enhanced the anti-tumor activity of SN-38 in CRC cells with wild type (WT) p53. Subsequently, we identified a potential mechanism of this cooperative interaction by showing that CQ and SN-38 acted together to trigger reactive oxygen species (ROS) burst, upregulate p53 expression, elicit the loss of lysosomal membrane potential (LMP) and mitochondrial membrane potential (∆ψm). In addition, ROS induced by CQ plus SN-38 upregulated p53 levels by activating p38, conversely, p53 stimulated ROS. These results suggested that ROS and p53 reciprocally promoted each other's production and cooperated to induce CRC cell death. Moreover, we showed induction of ROS and p53 by the two agents provoked the loss of LMP and ∆ψm. Altogether, all results suggested that CQ synergistically sensitized human CRC cells with WT p53 to SN-38 through lysosomal and mitochondrial apoptotic pathway via p53-ROS cross-talk. Lastly, we showed that CQ could enhance CRC cells response to CPT-11 (a prodrug of SN-38) in xenograft models. Thus the combined treatment might represent an attractive therapeutic strategy for the treatment of CRC.

Sulfated Glycans and Related Digestive Enzymes in the Zika Virus Infectivity: Potential Mechanisms of Virus-Host Interaction and Perspectives in Drug Discovery.

As broadly reported, there is an ongoing Zika virus (ZIKV) outbreak in countries of Latin America. Recent findings have demonstrated that ZIKV causes severe defects on the neural development in fetuses in utero and newborns. Very little is known about the molecular mechanisms involved in the ZIKV infectivity. Potential therapeutic agents are also under investigation. In this report, the possible mechanisms of action played by glycosaminoglycans (GAGs) displayed at the surface proteoglycans of host cells, and likely in charge of interactions with surface proteins of the ZIKV, are highlighted. As is common for the most viruses, these sulfated glycans serve as receptors for virus attachment onto the host cells and consequential entry during infection. The applications of (1) exogenous sulfated glycans of different origins and chemical structures capable of competing with the virus attachment receptors (supposedly GAGs) and (2) GAG-degrading enzymes able to digest the virus attachment receptors on the cells may be therapeutically beneficial as anti-ZIKV. This communication attempts, therefore, to offer some guidance for the future research programs aimed to unveil the molecular mechanisms underlying the ZIKV infectivity and to develop therapeutics capable of decreasing the devastating consequences caused by ZIKV outbreak in the Americas.

Abstract P184: Co-localization and Natriuretic Interdependence of Angiotensin AT2R and MasR in Obese Rat Kidney

The actions of angiotensin II type 2 receptor (AT 2 R) and receptor mas (MasR) are complex but show similar pro-natriuretic function; particularly AT 2 R expression and natriuretic function are enhanced in obese/diabetic rat kidney. In light of previous reports, we tested hypothesis that AT 2 R and MasR are interdependent to produce natriuresis in obese rats due to potential physical interaction. Infusion of AT 2 R agonist C21 (5 μg/kg/min) in obese Zucker rats (OZR) caused diuresis/natriuresis which were attenuated by simultaneous infusion of the AT 2 R antagonist PD123319 (50 μg/kg/min) or the MasR antagonist A-779 (50 μg/kg/min). Similarly, infusion of MasR agonist Ang-(1-7) (110 fmol/kg/min) in OZR caused diuresis/netriuresis, which were attenuated by simultaneous infusion of A-779 or PD123319. Dual labeling of AT 2 R and MasR in OZR kidney slices revealed four-fold co-localization of AT 2 R and MasR (9.83 vs. 2.50 dual labeled cells/1600 μm 2 ) compared with lean rats in which AT 2 R is not natriuretic. Moreover, the AT 2 R co-immunoprecipitates with MasR in cortical homogenate of OZR. Immunoblotting of AT 2 R and MasR with zero length oxidative (sulfhydryl groups) cross-linker cupric-phenanthroline in OZR cortical homogenate revealed a shift of AT 2 R (~62 kDa) and MasR (~54 kDa) bands upward with overlapping migration for their complexes (~160 kDa and 245 kDa) which were sensitive to the reducing β-mercaptoethanol. Similar observations were made in HK-2 cells, where glucose (25 mM) treatment enhanced the crosslinking. Collectively, the study reveals AT2R and MasR are co-localized and functionally interdependent in producing natriuretic response. Hyperglycemic oxidative stress affecting sulfhydryl groups present a potential mechanism of such physical interaction between these receptors. (Support: R01DK061578)

Abstract 4540: Use of SIAH E3 ubiquitin ligase as a biomarker in pancreatic adenocarcinoma

Abstract The dismal prognosis of patients diagnosed with pancreatic cancer points to our limited arsenal of effective anticancer therapies. Oncogenic K-RAS pathway activation is commonly detected in pancreatic cancer. These activations confer drug resistance, drive aggressive tumor growth and metastasis, and ultimately contribute to poor clinical outcome. Currently, there is no curative treatments for pancreatic cancers. Thus, early detection, biomarker discovery, and identifying novel means of countervailing hyperactive K-RAS signals are urgently needed. Seven-In-Absentia Homolog (SIAH), E3 ubiquitin ligase, is an essential downstream component of the RAS signal transduction pathway. SIAH is a member of a highly evolutionarily conserved family of RING finger E3 ubiquitin ligases. Our previous immunohistochemistry (IHC) studies have shown SIAH is a tumor-specific biomarker and SIAH expression is progressively increased as pancreatic tumor progresses from pancreatic intraepithelial neoplasia (PanIN) to pancreatic adenocarcinoma (PDCA) at late stages. In this study, we expand our observations by comparing the expression patterns of SIAH and several newly identified SIAH-interacting proteins using Mayo clinic pancreatic cancer SPORE tissue microarrays (TMA) in a hope of identifying new vulnerability and novel prognostic biomarkers in pancreatic cancer. We hypothesized that SIAH and SIAH-interacting proteins may serve as useful biomarkers and will help to assess effectiveness of anticancer treatment, disease progress, predict clinical outcome and patient survival in the clinical settings. Moreover, we are evaluating SIAH's role in the regulation of the SIAH-interacting proteins and validating the potential mechanisms of these dynamic interactions identified in vitro using pancreatic cancer patients TMA. Ultimately, we aim to explore the new cancer vulnerability, develop new therapeutic strategies, and validate novel prognostic biomarkers for pancreatic cancer patients. This study is performed in a double blind control settings and we are currently awaiting the disclosure of the clinical information from the pathologist. Citation Format: Elizaevta Svyatova. Use of SIAH E3 ubiquitin ligase as a biomarker in pancreatic adenocarcinoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4540.

Interaction of Giardia intestinalis and Systemic Oxidation in Preschool Children in the Western Highlands of Guatemala.

Guatemala is a country with the highest prevalence of stunting in under-5 children in the Americas, with a national average of 49.8%. Asymptomatic intestinal colonization with Giardia intestinalis is common in Guatemalan preschoolers and has been implicated as a factor in linear growth retardation. The potential mechanisms of any giardiasis-growth interaction have not been exhaustively explored. The aim of the present study was to describe urine oxidative stress biomarkers and erythrocyte antioxidant enzyme activity, and to explore any association with prevalence or intensity of G intestinalis infection in preschoolers attending 3 government-subsidized day care centers in the Guatemalan Western Highlands. Samples of feces, urine, and red blood cell (RBC) hemolysate were collected in a total of 74 preschoolers enrolled in 3 day care centers. Giardia prevalence and a proxy index for intensity were assessed by enzyme-linked immunosorbent assay (ELISA). Urinary biomarkers of oxidative damage to DNA (8-hydroxydeoxyguanosine [8-OHdG]) and to lipid (F2t 15-Isoprostane [F2-Iso]) were measured by ELISA. The erythrocyte activity of catalase (CAT), superoxide dismutase (SOD), glutathione reductase (GSR), and glutathione peroxidase (GPX) were measured by respective spectroscopic substrate-based reaction assays. Median values of RBC CAT activity (P = 0.016) and urine F2-Iso (P = 0.023) differed between children who were positive (n = 39) and negative (n = 35) for Giardia. Similarly, G intestinalis intensity was significantly and positively associated with urinary F2-Iso (r = 0.446, P < 0.001), RBC SOD (r = 283, P = 0.014), and RBC CAT (r = 0.260, P = 0.025). The optical density reading of the fecal ELISA assay for G intestinalis has potential as a proxy for the intensity of infestation. In this respect, there exists an association of this intensity with indicators of the systemic oxidation.

The Association between Resting Functional Connectivity and Visual Creativity

Resting-state functional connectivity (RSFC), the temporal correlation of intrinsic activation between different brain regions, has become one of the most fascinating field in the functional imaging studies. To better understand the association between RSFC and individual creativity, we used RSFC and the figure Torrance Tests of Creative Thinking (TTCT-F) to investigate the relationship between creativity measured by TTCT and RSFC within two different brain networks, default mode network and the cognitive control network, in a large healthy sample (304). We took the medial prefrontal cortex (MPFC) and the bilateral dorsolateral prefrontal cortices (DLPFC) to be the seed regions and investigated the association across subjects between the score of TTCT-F and the strength of RSFC between these seed regions and other voxels in the whole brain. Results revealed that the strength of RSFC with the MPFC was significantly and negatively correlated with the score of TTCT-F in the precuneus. Meanwhile, we also found that the strength of RSFC with the left DLPFC was significantly and positively correlated with the score of TTCT-F in the right DLPFC. It suggests that the decreased RSFC within DMN and the increased RSFC within CCN presents a potential interaction mechanism between different region for higher creativity.

ChemInform Abstract: Water Purification: Adsorption over Metal‐Organic Frameworks

AbstractReview: 124 refs.

Effects of 6-Shogaol, A Major Component of Zingiber officinale Roscoe, on Human Cytochrome P450 Enzymes in vitro

Background : Ginger has been extensively used in foods and traditional medicines in Asian countries. Despite its frequent consumption in daily life, the mechanism of potential interactions between ginger components-drug has not been examined. To elucidate the mechanism of governing the effects of 6-shogaol, a primary constituent of dried ginger, on human cytochrome P450 (CYP) isoenzymes an incubation studies were carried out using pooled human liver microsome (HLM). Methods and Results : CYP isoenzyme specific substrate was incubated with multiple concentrations of inhibitor, HLM and cofactors. 6-shogaol showed a potent inhibitory effect on CYP2C9, CYP1A2 and CYP2C19 with half maximal inhibitory concentration () values of 29.20, 20.68 and respectively. To estimate the value of the inhibition constant () and the mode of inhibition, an incubation study with varying concentrations of each CYP isoenzyme-specific probe was performed. 6-shogaol inhibited CYP2C9 and CYP2C19 noncompetitively ($K_i

QSAR Toolbox – workflow and major functionalities

The OECD QSAR Toolbox is a software application intended to be used by governments, the chemical industry and other stakeholders in filling gaps in (eco)toxicity data needed for assessing the hazards of chemicals. The development and release of the Toolbox is a cornerstone in the computerization of hazard assessment, providing an ‘all inclusive’ tool for the application of category approaches, such as read-across and trend analysis, in a single software application, free of charge. The Toolbox incorporates theoretical knowledge, experimental data and computational tools from various sources into a logical workflow. The main steps of this workflow are substance identification, identification of relevant structural characteristics and potential toxic mechanisms of interaction (i.e. profiling), identification of other chemicals that have the same structural characteristics and/or mechanism (i.e. building a category), data collection for the chemicals in the category and use of the existing experimental data to fill the data gap(s). The description of the Toolbox workflow and its main functionalities is the scope of the present article.

Adsorption Studies of Organophosphonic Acids on Differently Activated Gold Surfaces.

In this study, the formation of self-assembled monolayers consisting of three organophosphonic acids (vinyl-, octyl-, and tetradecylphosphonic acid) from isopropanol solutions onto differently activated gold surfaces is studied in situ and in real time using multiparameter surface plasmon resonance (MP-SPR). Data retrieved from MP-SPR measurements revealed similar adsorption kinetics for all investigated organophosphonic acids (PA). The layer thickness of the immobilized PA is in the range of 0.6-1.8 nm corresponding to monolayer-like coverage and correlates with the length of the hydrocarbon chain of the PA molecules. After sintering the surfaces, the PA are irreversibly attached onto the surfaces as proven by X-ray photoelectron spectroscopy and attenuated total reflection infrared and grazing incidence infrared spectroscopy. Potential adsorption modes and interaction mechanisms are proposed.

Water Purification: Adsorption over Metal‐Organic Frameworks

AbstractWater pollution relating to human beings' health is a universal problem across community society. Highly efficient, economically feasible and easily achievable approaches are long‐sought‐after for water purification. Adsorption processes with porous materials (e.g. zeolites, activated carbon, silica gel, metal‐organic frameworks (MOFs)) have drawn much attention in this field during past decades. In it, MOFs with numerous active sites, uniform porosity and tailorable structure diversity are arising to be one of the most promising adsorbents for water purification. During the adsorption processes, influence factors that determine or affect the usability and performances of MOFs are mainly focused on the stability of MOFs, their affinity for contaminants and the conducting conditions (pH, initial concentration of the contaminants). In this review, we will systematically present the performances of MOFs (mainly focused on MOF crystals, MOF nanomaterial or MOF composites will be beyond the scope of this review) for contaminants purification (inorganic and organic contaminants) in water and give a detailed discussion about the connection among their performances, conducting condition factors and potential interaction mechanisms (e.g. electrostatic interactions, coordination or p‐p interaction). We hope this review will be beneficial to the design, regeneration and reuse of MOF adsorbents and promote the development of MOFs for water purification.

Mechanism of Interaction between Adenosine Phosphates and Lysenin Channels

Lysenin, a 297 amino acid pore forming toxin extracted from the earthworm E. foetida, inserts hexameric channels in natural and artificial membranes containing sphingomyelin. A distinct feature of lysenin channels is their asymmetric voltage induced gating which occurs at low positive transmembrane potentials. Although the structure of the channel is not yet solved, previous studies of the lysenin monomeric structure and interaction with membranes indicate the presence of local positive charges within the protein's structure. Consequently, we hypothesized that highly charged organic anions such as ATP, ADP, and AMP may interact with the channel and alter its functionality. Here we show that the macroscopic conductance of the channels was diminished by addition of various adenosine phosphates in a charge and concentration-dependent manner. Single channel explorations have shown a gradual reduction of the ionic currents indicating interaction with absence of gating. Buffer-exchange experiments demonstrated that the current inhibition is reversible, pointing out a potential electrostatic mechanism of interaction between channels and anions which implies binding. This hypothesis was further sustained by analyzing the inhibitory effects of ATP comprising ionic solutions with different ionic strengths. Hill analysis provided further insights into the inhibition process and indicated a positive cooperativity between binding events. In addition, the I-V plots recorded in the presence of increasing inhibitor concentration demonstrate a significant rightward shift of the voltage-induced gating profile. The reduced effects elicited by AMP as compared with ATP and ADP, the reversibility of the inhibition, and the strong dependency of the observed effects on the ionic strength point out an electrostatic mechanism of interaction which may yield partial occlusion of the channels and modulation of the voltage-induced gating. This work sets an example of purinergic signaling that implies modulating the functionality of an exogenous membrane transporter.

Interaction mechanisms and structural properties of B-, Si-doped C60 fullerenes with 1-formylpiperazine

AbstractPiperazines and fullerene nanocages are versatile compounds. These are discussed in a wide range of academic work, especially in the field of medicine, and considered for various applications by the pharmaceutical industry. In the present research, the potential interaction mechanisms between B-, Si-doped C60 and 1-formylpiperazine (1-fp) were examined within the framework of density functional theory, along with their optimized molecular structures and electronic properties. The calculated binding energies and various other physical and chemical parameters of 1-fp found in this work in comparison with the Si- and B-doped fullerenes suggest that doping of fullerene nanocage leads to a strong interaction mechanism that alters the chemical and electronic properties of the investigated compounds. This finding can be used as a guide for their further applications.

The role of respiratory viruses in the etiology of bacterial pneumonia: An ecological perspective.

Pneumonia is the leading cause of death among children less than 5 years old worldwide. A wide range of viral, bacterial and fungal agents can cause pneumonia: although viruses are the most common etiologic agent, the severity of clinical symptoms associated with bacterial pneumonia and increasing antibiotic resistance makes bacterial pneumonia a major public health concern. Bacterial pneumonia can follow upper respiratory viral infection and complicate lower respiratory viral infection. Secondary bacterial pneumonia is a major cause of influenza-related deaths. In this review, we evaluate the following hypotheses: (i) respiratory viruses influence the etiology of pneumonia by altering bacterial community structure in the upper respiratory tract (URT) and (ii) respiratory viruses promote or inhibit colonization of the lower respiratory tract (LRT) by certain bacterial species residing in the URT. We conducted a systematic review of the literature to examine temporal associations between respiratory viruses and bacteria and a targeted review to identify potential mechanisms of interactions. We conclude that viruses both alter the bacterial community in the URT and promote bacterial colonization of the LRT. However, it is uncertain whether changes in the URT bacterial community play a substantial role in pneumonia etiology. The exception is Streptococcus pneumoniae where a strong link between viral co-infection, increased carriage and pneumococcal pneumonia has been established.

Hydrogen sulfide: a versatile regulator of environmental stress in plants

In mammalian cells, hydrogen sulfide (H2S) has been identified as the third gasotransmitter after nitric oxide and carbon monoxide. Overwhelming evidence has proven that H2S also participates in diverse physiological and biochemical processes within the organism and exert specific functions in plants. A number of reports illustrated that H2S could improve plants ability of adapting to the multiple environmental stimuli by alleviating injuries and toxicities caused by the stressful conditions. It also participated in specific physiological, developmental and metabolic processes, such as the regulation of stomatal movement and drought tolerance, senescence and maturation, and lateral root formation. In this article, latest research progresses in biosynthetic and metabolic pathways of H2S in plants as well as corresponding physiological functions were summarized. We also discussed the potential molecular mechanism of interaction between H2S and other signaling molecules as well as the H2S-modifying protein activities. Finally, we prospected possible future work for H2S in plants.

Calcitriol and 20(S)-protopanaxadiol synergistically inhibit growth and induce apoptosis in human prostate cancer cells

The potential cancer preventive roles of calcitriol, the dihydroxylated metabolite of Vitamin D3, as well as 20(S)-protopanaxadiol (aPPD), the aglycone of the protopanaxadiol family of ginsenosides, have gained much attention in recent years for the prevention/treatment of prostate cancer (PCa). In the present study, we evaluated the anticancer and chemosensitization effects of calcitriol at clinically relevant concentrations and aPPD, either alone or in combination, in two well-characterized human PCa cell lines: androgen-sensitive non-metastatic LNCaP cells and androgen-independent metastatic C4-2 cells. The effects of the treatments on PCa cell viability and proliferation rates were evaluated by MTS and Brdu assays, respectively. Combination Indices (CI) and Dose Reduction Indices (DRI) were estimated to assess synergistic anticancer activity using Calcusyn software (Biosoft, Cambridge, UK). Then, we determined the potential Pharmacodynamic interaction mechanisms as follows: The protein expression levels of the genes those are known to control cell cycle (cyclin D1 and cdk2); apoptosis (Bcl-2, Bax, and Capspases 3), androgen receptor and Vitamin D receptors were examined upon combinational treatment. The cell viability assay data show that addition of 10nM calcitriol to aPPD significantly lowered its IC50 values from the range of 41–53μM to 13–23μM, in LNCaP and C4-2 prostate cancer cells. The cell proliferation rate was significantly lower for combination treatments compared to the cells treated with aPPD alone. Similarly, Western blot results indicate that aPPD significantly upregulated Vitamin D receptor (VDR) expression, while calcitriol further enhanced the ability of aPPD to induce pro-apoptotic BAX, increased cleaved caspase-3 and downregulate cdk2 protein levels. Thus, the pharmacodynamic interaction between aPPD and calcitriol in impacting growth inhibition and apoptosis appears to be synergistic in nature. In conclusion, calcitriol sensitizes PCa cells to aPPD-mediated anticancer effects by enhancing its ability to induce apoptosis and reduce cell proliferation, and this synergism may limit calcitriol toxicity by facilitating the use of lower calcitriol doses. The associated increase in VDR expression and calcitriol half-life may be mechanistically associated with this sensitization effect.

A high-resolution gene expression atlas of epistasis between gene-specific transcription factors exposes potential mechanisms for genetic interactions.

BackgroundGenetic interactions, or non-additive effects between genes, play a crucial role in many cellular processes and disease. Which mechanisms underlie these genetic interactions has hardly been characterized. Understanding the molecular basis of genetic interactions is crucial in deciphering pathway organization and understanding the relationship between genotype, phenotype and disease.ResultsTo investigate the nature of genetic interactions between gene-specific transcription factors (GSTFs) in Saccharomyces cerevisiae, we systematically analyzed 72 GSTF pairs by gene expression profiling double and single deletion mutants. These pairs were selected through previously published growth-based genetic interactions as well as through similarity in DNA binding properties. The result is a high-resolution atlas of gene expression-based genetic interactions that provides systems-level insight into GSTF epistasis. The atlas confirms known genetic interactions and exposes new ones. Importantly, the data can be used to investigate mechanisms that underlie individual genetic interactions. Two molecular mechanisms are proposed, “buffering by induced dependency” and “alleviation by derepression”.ConclusionsThese mechanisms indicate how negative genetic interactions can occur between seemingly unrelated parallel pathways and how positive genetic interactions can indirectly expose parallel rather than same-pathway relationships. The focus on GSTFs is important for understanding the transcription regulatory network of yeast as it uncovers details behind many redundancy relationships, some of which are completely new. In addition, the study provides general insight into the complex nature of epistasis and proposes mechanistic models for genetic interactions, the majority of which do not fall into easily recognizable within- or between-pathway relationships.Electronic supplementary materialThe online version of this article (doi:10.1186/s12915-015-0222-5) contains supplementary material, which is available to authorized users.

Synergistic induction of apoptosis by salinomycin and gefitinib through lysosomal and mitochondrial dependent pathway overcomes gefitinib resistance in colorectal cancer.

Here, we showed the antibiotic salinomycin (SAL) combined with GEF exerted synergistic cytotoxicity effects in colorectal cancer cells irrespective of their EGFR and KRAS status, with a relatively low toxicity to normal cells. Additionally, combination of the two drugs overcame Ras-induced resistance and the acquired resistance to GEF. Further, we identified a new potential mechanism of this cooperative interaction by showing that GEF and SAL acted together to enhance production of reactive oxygen species (ROS), loss of mitochondrial membrane potential (MMP) and lysosomal membrane potential (LMP). And the ROS contributed the loss of MMP and LMP. We also found that GEF and SAL acted in concert to induce apoptosis via a mitochondrial-lysosomal cross-talk and caspase-independent pathway triggered by cathepsin B and D. Lastly, SAL in combination with GEF sensitized GEF-resistant cells to GEF in a nude mouse xenograft model. This novel combination treatment might provide a potential clinical application to overcome GEF resistance in colorectal cancer.