Mechanistic-Based Classification of Endocytosis-Related Inhibitors: Does It Aid in Assigning Drugs against SARS-CoV-2?

Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) canonically utilizes clathrin-mediated endocytosis (CME) and several other endocytic mechanisms to invade airway epithelial cells. Endocytic inhibitors, particularly those targeting CME-related proteins, have been identified as promising antiviral drugs. Currently, these inhibitors are ambiguously classified as chemical, pharmaceutical, or natural inhibitors. However, their varying mechanisms may suggest a more realistic classification system. Herein, we present a new mechanistic-based classification of endocytosis inhibitors, in which they are segregated among four distinct classes including: (i) inhibitors that disrupt endocytosis-related protein-protein interactions, and assembly or dissociation of complexes; (ii) inhibitors of large dynamin GTPase and/or kinase/phosphatase activities associated with endocytosis; (iii) inhibitors that modulate the structure of subcellular components, especially the plasma membrane, and actin; and (iv) inhibitors that cause physiological or metabolic alterations in the endocytosis niche. Excluding antiviral drugs designed to halt SARS-CoV-2 replication, other drugs, either FDA-approved or suggested through basic research, could be systematically assigned to one of these classes. We observed that many anti-SARS-CoV-2 drugs could be included either in class III or IV as they interfere with the structural or physiological integrity of subcellular components, respectively. This perspective may contribute to our understanding of the relative efficacy of endocytosis-related inhibitors and support the optimization of their individual or combined antiviral potential against SARS-CoV-2. However, their selectivity, combined effects, and possible interactions with non-endocytic cellular targets need more clarification.

Anticancer Effects of Combination of Indole-3-Carbinol and Hydroxychloroquine on Ehrlich Ascites Carcinoma via Targeting Autophagy and Apoptosis.

Indole-3-carbinol (I3C) is an active component of cruciferous vegetables which is considered a promising antineoplastic agent. This study aimed to assess I3C antineoplastic activity alone and with hydroxychloroquine (HCQ) on Ehrlich ascites carcinoma (EAC) model. Eighty female mice were divided into six groups wherein all groups except groups I and II received EAC cells (106 cells/mouse i.p.). Group I, served as control; group II served as I3C; group III served as EAC; groups IV and V received I3C (250 mg/kg body weight oral), and HCQ (60 mg/kg body weight i.p.) respectively; GVI received both I3C and HCQ. Antitumor response markers, serum, hepatic and renal biochemical parameters, histopathological changes, as well as autophagy and apoptosis markers in EAC cells were analyzed. The combination of I3C and HCQ showed the best antitumor responses with increased survival time and ameliorated biochemical parameters. Moreover, I3C upregulated LC3B and downregulated p62 gene expression in EAC cells. Furthermore, I3C combined with HCQ induced apoptosis by highly upregulating cleaved caspase-3 and Bax while downregulating Bcl-2 proteins expression in EAC cells in comparison with each drug alone. In conclusion, I3C combined with HCQ exhibited better antitumor activities than each drug alone via targeting autophagy and apoptosis.

Trichostatin A sensitizes hepatoma cells to Taxol more than 5-Aza-dC and dexamethasone.

OBJECTIVES: This work was designed to compare the sensitizing effects of epigenetic modifiers on cancer cells vs. that of glucocorticoids. Also, to evaluate their effects on genes involved in epigenetic changes and drug metabolism. METHODS: Hepatoma cells (HepG2) were treated with the anticancer drug (Taxol), with a histone deacetylase inhibitor (Trichostatin A [TSA]), DNA methyltransferase inhibitor (5-Aza-dC) or dexamethasone (DEX). Cytotoxicity was assessed by MTT assay and the apoptosis was determined by Annexin V-FITC. The expression levels of HDAC1, HDAC3, Dnmt1, Dnmt3α, CYP1A2, CYP3A4, CYP2B6, CYP2C19 and CYP2D6 were monitored by qRT-PCR. RESULTS: TSA, synergistically enhanced cells sensitivity with the anticancer effect of Taxol more than 5-Aza-dC and DEX. This was evidenced by the relative decrease in IC50 in cells cotreated with Taxol + TSA, Taxol + 5-Aza-dC or Taxol + DEX. Apoptosis was induced in 51.2, 16.9 and 41.3% of cells, respectively. In presence of Taxol, TSA induced four-fold increase in the expression of HDAC1 and downregulated Dnmt1&3α genes. CYP2D6 demonstrated progressive expression (up to 28-fold) with the increasing number of drugs. Moreover, the isoform overexpressed in cells treated with TSA + Taxol > DEX + Taxol > 5-Aza-dC + Taxol (6.4, 4.6 and 2.99, respectively). The investigated genes were clustered in two distinct subsets, where no coregulation was observed between HDAC1 and HDAC3. However, tight pairwise correlation-based cluster was seen between (CYP3A4/Dnmt3α and CYP2D6/CYP2C19). CONCLUSIONS: The data reflects the sensitizing effect of acetylation modification by TSA on the responsiveness of hepatoma cells to anticancer therapy. The effect of histone deacetylase inhibition was more than hypomethylation and glucocorticoid effects. TSA exerts its role through its modulatory role on epigenetics and drugs metabolizing genes. Other modifiers (5-Aza-dC and DEX), however may adopt different mechanisms.

Management of oxidative stress and inflammation in cardiovascular diseases: mechanisms and challenges.

Cardiovascular diseases (CVDs) have diverse physiopathological mechanisms with interconnected oxidative stress and inflammation as one of the common etiologies which result in the onset and development of atherosclerotic plaques. In this review, we illustrate this strong crosstalk between oxidative stress, inflammation, and CVD. Also, mitochondrial functions underlying this crosstalk, and various approaches for the prevention of redox/inflammatory biological impacts will be illustrated. In part, we focus on the laboratory biomarkers and physiological tests for the evaluation of oxidative stress status and inflammatory processes. The impact of a healthy lifestyle on CVD onset and development is displayed as well. Furthermore, the differences in oxidative stress and inflammation are related to genetic susceptibility to cardiovascular diseases and the variability in the assessment of CVDs risk between individuals; Omics technologies for measuring oxidative stress and inflammation will be explored. Finally, we display the oxidative stress-related microRNA and the functions of the redox basis of epigenetic modifications.

Evaluation of MicroRNA92, MicroRNA638 in Acute Lymphoblastic Leukemia of Egyptian Children.

OBJECTIVE: miRNA considers a small non-coding RNA molecule that has tumor suppressor or oncogenic functions and regulates gene expression. miRNA may be involved in the pathogenesis of acute lymphoblastic leukemia (ALL).  miRNA was evaluated in patients with ALL to correlate their importance in the clinical prediction and the response to chemotherapy. SUBJECT AND METHODS: The study population included 30 healthy control and 71 children with ALL is divided into 4 groups: healthy, newly diagnosed, remitted, and relapsed groups. We quantify miRNA 92a, miRNA 638 expression using real-time PCR in childhood ALL. RESULTS: plasma miRNA 92a and miRNA 638 expressions were elevated in ALL cases at the time of diagnosis (2.51 and 2.19 folds), and relapsed (2.1 and 1.61 folds) than that of patients with remitted ALL. There was a positive correlation between miRNA 92a and miRNA 638 patients with ALL. Also, total leukocyte and blast correlated with miRNA 92a and miRNA 638 unlike hemoglobin, and platelets didn't correlate with miRNA 92a and miRNA 638. The sensitivity of miRNA 92a and miRNA 638 were 41.5% and 54.7% respectively while the specificity was 100 % of miRNA 92a and miRNA 638. CONCLUSION: miRNA 92a and miRNA 638 are recommended to be used as potential predictive and follow-up markers in children with ALL remitted and relapsed cases.

Trichostatin A sensitizes hepatoma cells to Taxol more than 5-Aza-dC and dexamethasone.

OBJECTIVES: This work was designed to compare the sensitizing effects of epigenetic modifiers on cancer cells vs. that of glucocorticoids. Also, to evaluate their effects on genes involved in epigenetic changes and drug metabolism. METHODS: Hepatoma cells (HepG2) were treated with the anticancer drug (Taxol), with a histone deacetylase inhibitor (Trichostatin A [TSA]), DNA methyltransferase inhibitor (5-Aza-dC) or dexamethasone (DEX). Cytotoxicity was assessed by MTT assay and the apoptosis was determined by Annexin V-FITC. The expression levels of HDAC1, HDAC3, Dnmt1, Dnmt3α, CYP1A2, CYP3A4, CYP2B6, CYP2C19 and CYP2D6 were monitored by qRT-PCR. RESULTS: TSA, synergistically enhanced cells sensitivity with the anticancer effect of Taxol more than 5-Aza-dC and DEX. This was evidenced by the relative decrease in IC50 in cells cotreated with Taxol + TSA, Taxol + 5-Aza-dC or Taxol + DEX. Apoptosis was induced in 51.2, 16.9 and 41.3% of cells, respectively. In presence of Taxol, TSA induced four-fold increase in the expression of HDAC1 and downregulated Dnmt1&3α genes. CYP2D6 demonstrated progressive expression (up to 28-fold) with the increasing number of drugs. Moreover, the isoform overexpressed in cells treated with TSA + Taxol > DEX + Taxol > 5-Aza-dC + Taxol (6.4, 4.6 and 2.99, respectively). The investigated genes were clustered in two distinct subsets, where no coregulation was observed between HDAC1 and HDAC3. However, tight pairwise correlation-based cluster was seen between (CYP3A4/Dnmt3α and CYP2D6/CYP2C19). CONCLUSIONS: The data reflects the sensitizing effect of acetylation modification by TSA on the responsiveness of hepatoma cells to anticancer therapy. The effect of histone deacetylase inhibition was more than hypomethylation and glucocorticoid effects. TSA exerts its role through its modulatory role on epigenetics and drugs metabolizing genes. Other modifiers (5-Aza-dC and DEX), however may adopt different mechanisms.

ß-Arrestin inhibition induces autophagy, apoptosis, G0/G1 cell cycle arrest in agonist-activated V2R receptor in breast cancer cells.

Non-visual arrestins (ß-arrestins) are endocytic proteins that mediate agonist-activated GPCRs internalization and signaling pathways in an independent manner. The involvement of ß-arrestins in cancer invasion and metastasis is increasingly reported. So, it is hypothesized that inhibition of ß-arrestins may diminish the survival chances of cancer cells. This study aimed to evaluate the in vitro impact of inhibiting ß-arrestins on the autophagic and/or apoptotic responsiveness of breast cancer cells. We used Barbadin to selectively inhibit ß-Arr/AP2 interaction in AVP-stimulated V2R receptor of triple-negative breast cancer cells (MDA MB-231). Autophagy was assessed by the microtubule-associated protein 1 light chain 3-II (LC3II), apoptosis was measured by Annexin-V/PI staining and cell cycle distribution was investigated based upon the DNA content using flow cytometry. Barbadin reduced cell viability to 69.1% and increased the autophagy marker LC3II and its autophagic effect disappeared in cells transiently starved in Earle's balanced salt solution (EBSS). Also, Barbadin mildly enhanced the expression of P62 mRNA and arrested 63.7% of cells in G0/G1 phase. In parallel, the drug-induced apoptosis in 29.9% of cells (by AV/PI) and 27.8% of cells were trapped in sub-G1 phase. The apoptotic effect of Barbadin was enhanced when autophagy was inhibited by the PI3K inhibitor (Wortmannin). Conclusively, the data demonstrate the dual autophagic and apoptotic effects of ß-ßArr/AP2 inhibition in triple-negative breast cancer cells. These observations nominate ß-Arrs as selective targets in breast cancer treatment.

Synthesis, In Silico and In Vitro Assessment of New Quinazolinones as Anticancer Agents via Potential AKT Inhibition.

A series of novel quinazolinone derivatives (2-13) was synthesized and examined for their cytotoxicity to HepG2, MCF-7, and Caco-2 in an MTT assay. Among these derivatives, compounds 4 and 9 exhibited significant cytotoxic activity against Caco-2, HepG2, and MCF-7 cancer cells. Compound 4 had more significant inhibitory effects than compound 9 on Caco-2, HepG2, and MCF-7 cell lines, with IC50 values of 23.31 ± 0.09, 53.29 ± 0.25, and 72.22 ± 0.14µM, respectively. The AKT pathway is one of human cancer's most often deregulated signals. AKT is also overexpressed in human cancers such as glioma, lung, breast, ovarian, gastric, and pancreas. A molecular docking study was performed to analyze the inhibitory action of newly synthetic quinazolinone derivatives against Homo sapiens AKT1 protein. Molecular docking simulations were found to be in accordance with in vitro studies, and hence supported the biological activity. The results suggested that compounds 4 and 9 could be used as drug candidates for cancer therapy via its potential inhibition of AKT1 as described by docking study.

Propolis Potentiates Methotrexate Anticancer Mechanism and Reduces its Toxic Effects.

Egyptian propolis is a powerful antioxidant and free radical scavenger produced by bees. The current study was designed to characterize Egyptian propolis, investigate its anticancer effect in vitro and its protective role against methotrexate (MTX) toxicity in Ehrlich ascites carcinoma (EAC) experimental model. Our results revealed a high content of total phenolics, flavonoids and dihydroflavonols in propolis ethanolic extract (PEE). PEE prompted cytotoxic effects in cancer cell lines and antitumor effects against EAC mice model by reducing tumor volume, count of viable tumor cells with a significant elevation in the life span as well as the mean survival time of mice. The hepatic and renal biochemical and toxicity parameters of EAC-bearing mice treated with MTX were improved by PEE. Also, it elevates the expression of Bax, caspase-3 and cytochrome-C and reduces the Bcl2 expression in EAC cells. Moreover, PEE with MTX induced cell cycle arrest at the G0/G1 phase. Interestingly, the combination of PEE with MTX showed potent apoptosis as shown by DNA fragmentation gel, comet assay and dihydrofolate reductase level (DHFR). These findings demonstrate that Egyptian propolis extract had high chemical diversity and different antioxidant effects. Also, it optimizes the antitumor potential of MTX and declined its toxic effects.

Identification of RNA aptamer which specifically interacts with PtdIns(3)P.

The phosphinositide PtdIns(3)P plays an important role in autophagy; however, the detailed mechanism of its activity remains unclear. Here, we used a Systematic Evolution of Ligands by EXponential enrichment (SELEX) screening approach to identify an RNA aptamer of 40 nucleotides that specifically recognizes and binds to intracellular lysosomal PtdIns(3)P. Binding occurs in a magnesium concentration- and pH-dependent manner, and consequently inhibits autophagy as determined by LC3II/I conversion, p62 degradation, formation of LC3 puncta, and lysosomal accumulation of Phafin2. These effects in turn inhibited lysosomal acidification, and the subsequent hydrolytic activity of cathepsin D following induction of autophagy. Given the essential role of PtdIns(3)P as a key targeting molecule for autophagy induction, identification of this novel PtdIns(3)P RNA aptamer provides new opportunities for investigating the biological functions and mechanisms of phosphoinositides.

The nephroprotective effects of allicin and ascorbic acid against cisplatin-induced toxicity in rats.

Cisplatin (CDDP) may induce nephrotoxicity through oxidative stress, DNA damage, and inflammation. This study was performed to evaluate the antioxidant and anti-inflammatory effects of allicin and ascorbic acid (AA) and investigate the nephroprotective efficacy of their combination against CDDP-induced intoxication. Rats were divided into seven groups: control, allicin (10 mg/kg for 14 days), AA (20 mg/kg for 14 days), CDDP (7 mg/kg as a single dose on the seventh experimental day), CDDP-allicin, CDDP-AA, and CDDP-allicin-AA (at the aforementioned doses). The administration of CDDP induced marked body weight loss and renal damage, manifested by significant increases (p < 0.05) in serum creatinine, urea, and uric acid levels and significant reductions in serum Na, Ca, and phosphorus concentrations, in addition to severe alterations in serum and renal tissue levels of tumor necrosis factor-α in comparison with control rats. Moreover, CDDP-intoxicated rats exhibited significantly (p < 0.05) higher lipid peroxidation, as well as lower levels of reduced glutathione and activities of glutathione peroxidase, superoxide dismutase, and catalase enzymes in the renal tissue, compared with control rats. The administration of allicin or AA significantly reduced (p < 0.05) the CDDP-induced changes in all the aforementioned parameters. Interestingly, allicin achieved comparable nephroprotection to AA in most assessed parameters; however, the restoration of normal serum and renal tissue concentrations of these parameters was more frequent in the CDDP-AA group. In conclusion, both allicin and AA showed significant nephroprotective effects against CDDP intoxication and their combination exhibited better protection than either agent alone. These results are probably mediated by their antioxidant and anti-inflammatory activities.

Functional characterization of lysosomal interaction of Akt with VRK2.

Serine-threonine kinase Akt (also known as PKB, protein kinase B), a core intracellular mediator of cell survival, is involved in various human cancers and has been suggested to play an important role in the regulation of autophagy in mammalian cells. Nonetheless, the physiological function of Akt in the lysosomes is currently unknown. We have reported previously that PtdIns(3)P-dependent lysosomal accumulation of the Akt-Phafin2 complex is a critical step for autophagy induction. Here, to characterize the molecular function of activated Akt in the lysosomes in the process of autophagy, we searched for the molecules that interact with the Akt complex at the lysosomes after induction of autophagy. By time-of-flight-mass spectrometry (TOF/MS) analysis, kinases of the VRK family, a unique serine-threonine family of kinases in the human kinome, were identified. VRK2 interacts with Akt1 and Akt2, but not with Akt3; the C terminus of Akt and the N terminus of VRK2 facilitate the interaction of Akt and VRK2 in mammalian cells. The kinase-dead form of VRK2A (KD VRK2A) failed to interact with Akt in coimmunoprecipitation assays. Bimolecular fluorescence complementation (BiFC) experiments showed that, in the lysosomes, Akt interacted with VRK2A but not with VRK2B or KD VRK2A. Immunofluorescent assays revealed that VRK2 and phosphorylated Akt accumulated in the lysosomes after autophagy induction. WT VRK2A, but not KD VRK2A or VRK2B, facilitated accumulation of phosphorylated Akt in the lysosomes. Downregulation of VRK2 abrogated the lysosomal accumulation of phosphorylated Akt and impaired nuclear localization of TFEB; these events coincided to inhibition of autophagy induction. The VRK2-Akt complex is required for control of lysosomal size, acidification, bacterial degradation, and for viral replication. Moreover, lysosomal VRK2-Akt controls cellular proliferation and mitochondrial outer-membrane stabilization. Given the roles of autophagy in the pathogenesis of human cancer, the current study provides a novel insight into the oncogenic activity of VRK2-Akt complexes in the lysosomes via modulation of autophagy.

Comparative study on the toxic effects of some heavy metals on the Nile Tilapia, Oreochromis niloticus, in the Middle Delta, Egypt.

Heavy metals are the most dangerous hazards affecting aquatic biota in Egypt specially the Nile Tilapia, Oreochromis niloticus, which is an important species in commercial fisheries. Some areas were not fully studied to screen the hazards that may affect this economic fish. Therefore, the present study aimed to evaluate the potential hazards of heavy metals on O. niloticus in Al-Gharbiya Governorate in the Middle delta of Egypt. Water and fish samples were collected from Al-Qased canal, Kafr El-Zayaat Nile, El-Maash canal in Al-Gharbiya Governorate plus a reference site which is a fish farm at the Faculty of Agriculture, Damietta University, Damitta Governorate, Egypt. The results showed a significant increase (p < 0.05) in the lead, zinc, magnesium, manganese, and copper levels while showed a significant decrease (p < 0.05) in the iron level in the water from all the investigated areas. Cadmium level was significantly high (p < 0.05) in Kafr El-Zayaat Nile and EL-Maash canal only. These metals were also accumulated in the fish livers and gills. Consequently, ALT and AST activities and creatinine level were significantly (p < 0.05) high in all the investigated areas. Histopathological examination revealed cytoplasmic and nuclear degeneration in the hepatocytes in all the investigated areas. Renal glomeruli and Bowman's capsule were not completely intact in Al-Qased and El-Maash canals while conspicuous shrinkage of the glomeruli was determined in Kafr El-Zayaat Nile. Furthermore, slight damage in the secondary lamellae was detected in the gill from Al-Qased canal while in the other areas appeared vacuolated or destructed. Finally, spleen sections of fish from different sites showed the absence of melanin pigments and some vacuoles. In conclusion, the Nile Tilapia, Oreochromis niloticus, is affected by the toxic effects of the heavy metals in Al-Gharbiya Governorate in Egypt and this gives an alarm and should be taken into consideration.

Amelioration effect of Egyptian sweet orange hesperidin on Ehrlich ascites carcinoma (EAC) bearing mice.

There are global increased interests to identify novel agents that can possess anti-tumor effects or maximize the anti-tumor effects of low doses for conventional anti-cancer drugs. The aim of this study was to investigate anti-tumor effects and protective role of isolated hesperidin from sweet orange on doxorubicin-induced toxicity in Ehrlich ascites carcinoma (EAC) bearing mice. Tumor cells were injected into Swiss albino mice followed by hesperidin administration either alone or in combination with doxorubicin. Biochemical parameters on serum and hepatic were measured. In addition, the effect of hesperidin on apoptotic genes (Caspase3 and Bax) and anti-apoptotic gene (Bcl2) on tumor cells were evaluated by RT- PCR. The results showed that addition of hesperidin to doxorubicin-induced higher anti-tumor responses than treatment with hesperidin or doxorubicin alone. Hesperidin and doxorubicin in combination prolonged the life span of EAC tumor-bearing mice which was associated with a decrease in the number of viable tumor cells and increases in dead tumor cells number. In addition, co-administration of hesperidin with doxorubicin ameliorated the alteration in serum ALT, AST, ALP, GGT and LDH activities, total protein, albumin, creatinine, urea and total lipids concentrations. Moreover, hesperidin alone and in combination with doxorubicin-treated group decreased hepatic, TBARS level significantly as compared with tumor bearing mice and doxorubicin treated group. In contrast, hesperidin alone and combined with doxorubicin ameliorated total antioxidant capacity, reduced glutathione level, and antioxidant enzymes activities such as GPx and CAT in liver tissues. Moreover, hesperidin induced apoptosis of tumor cells which appeared as DNA fragmentation by down-regulation of Bcl2 as anti-apoptotic gene and stimulation of Caspase3 and Bax genes expression as apoptotic genes. In conclusion, Egyptian citrus peels are a rich source of the antioxidant hesperidin. Moreover, it can ameliorate the cytotoxic effect of doxorubicin while enhancing its anti-tumor effect.

Phosphorylation-dependent Akt-Inversin interaction at the basal body of primary cilia.

A primary cilium is a microtubule-based sensory organelle that plays an important role in human development and disease. However, regulation of Akt in cilia and its role in ciliary development has not been demonstrated. Using yeast two-hybrid screening, we demonstrate that Inversin (INVS) interacts with Akt. Mutation in the INVS gene causes nephronophthisis type II (NPHP2), an autosomal recessive chronic tubulointerstitial nephropathy. Co-immunoprecipitation assays show that Akt interacts with INVS via the C-terminus. In vitro kinase assays demonstrate that Akt phosphorylates INVS at amino acids 864-866 that are required not only for Akt interaction, but also for INVS dimerization. Co-localization of INVS and phosphorylated form of Akt at the basal body is augmented by PDGF-AA Akt-null MEF cells as well as siRNA-mediated inhibition of Akt attenuated ciliary growth, which was reversed by Akt reintroduction. Mutant phosphodead- or NPHP2-related truncated INVS, which lack Akt phosphorylation sites, suppress cell growth and exhibit distorted lumen formation and misalignment of spindle axis during cell division. Further studies will be required for elucidating functional interactions of Akt-INVS at the primary cilia for identifying the molecular mechanisms underlying NPHP2.

Growth inhibition of human non-small lung cancer cells h460 by green tea and ginger polyphenols.

UNLABELLED: Non small cell lung cancer is known to resist apoptotic stimuli of various antitumor agents and become progressively incurable. The present study was undertaken to evaluate the in vitro antineoplastic effect of polyphenols extracted from both green tea (GTPs) and ginger (GPs) on non-small cell lung cancer cells (NSCLC-NCI-H460). METHODS: The direct antitumor effect of GTPs and GPs on H460 cells was assessed by investigating the proliferation rate, metabolic activity assay (MTT method) and the apoptotic effect (determined by an annexin V apoptosis assay). Also, the inhibition concentrations (IC50) of both extracts and the levels of P 53 and Bcl-2 proteins were determined. RESULTS: GTPs and GPs have inhibited the proliferation of H460 cells in a dose-dependent manner. At the end of treatment period (96 h) the cell population has decreased to 16% and 26% when treated with 80µg GTPs or GPs, respectively, compared to the untreated cells. The IC50 values of both extracts were 32.9 and 55.5 g/ml, respectively. GTPs was more effective in reduction of cell metabolic activity (measured by MTT assay), where cell count decreased to 22% compared to 64% in cells treated with similar concentration (80µg) of GPs. Lower concentration (20µg) of cisplatin induced 15% reduction in cell metabolic activity. Moreover, 80µg of GTPs and GPs extracts induced apoptosis by 71% and 39% of the living cells, respectively. The apoptotic effect of both extracts, especially GTPs, seems to be mediated by both P 53 and Bcl-2. CONCLUSION: The study reports the antiproliferative and apoptosis-mediated cytotoxic effects of green tea and ginger polyphenolic extracts on human H460 cell line, indicating their promising chemopreventive effect against lung cancer.