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Phosphoinositide 3-kinase (PI3K) pathway, controlling diverse functions in cells, is one of the most frequently dysregulated pathways in cancer. Several negative regulators have been reported to intricately constrain the overactivation of PI3K pathway. Phosphatidylinoinosidine-3-kinase interacting protein 1 (PIK3IP1), as a unique transmembrane protein, is a newly discovered negative regulator of PI3K pathway. PIK3IP1 negatively regulates PI3K activity by directly binding to the p110 catalytic subunit of PI3K. It has been reported that PIK3IP1 is frequently low expressed in tumors and autoimmune diseases. In tumor cells and impaired cardiomyocyte, PIK3IP1 inhibits cell proliferation and survival. Consistently, the expression of PIK3IP1 is related with the condition of cancer. In addition, PIK3IP1 inhibits the inflammatory response and immune function via maintaining the quiescent state of immune cells. Thus, low expression of PIK3IP1 represents the severe condition of autoimmune diseases. PIK3IP1 is regulated by transcription factors, epigenetic factors or micro-RNAs to facilitate its normal function in different cellular contexts. This review integrates the total findings on PIK3IP1 in different disease, and summaries the structure, biological functions and regulatory mechanisms of PIK3IP1.
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Neoplasias , Humanos , Animais , Neoplasias/patologia , Neoplasias/genética , Doenças Autoimunes/genética , Proteínas de Transporte/metabolismo , Proteínas de Transporte/genética , Transdução de Sinais , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas de Membrana , Peptídeos e Proteínas de Sinalização IntracelularRESUMO
Heat shock protein 90 (Hsp90) is a predominant member among Heat shock proteins (HSPs), playing a central role in cellular protection and maintenance by aiding in the folding, stabilization, and modification of diverse protein substrates. It collaborates with various co-chaperones to manage ATPase-driven conformational changes in its dimer during client protein processing. Hsp90 is critical in cellular function, supporting the proper operation of numerous proteins, many of which are linked to diseases such as cancer, Alzheimer's, neurodegenerative conditions, and infectious diseases. Recognizing the significance of these client proteins across diverse diseases, there is a growing interest in targeting Hsp90 and its co-chaperones for potential therapeutic strategies. This review described biological background of HSPs and the structural characteristics of HSP90. Additionally, it discusses the regulatory role of heat shock factor-1 (HSF-1) in modulating HSP90 and sheds light on the dynamic chaperone cycle of HSP90. Furthermore, the review discusses the specific contributions of HSP90 in various disease contexts, especially in cancer. It also summarizes HSP90 inhibitors for cancer treatment, offering a thoughtful analysis of their strengths and limitations. These advancements in research expand our understanding of HSP90 and open up new avenues for considering HSP90 as a promising target for therapeutic intervention in a range of diseases.
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Targeting the epidermal growth factor receptor (EGFR) has been recognized as an effective strategy for treating non-small-cell lung cancer (NSCLC). Although several representative EGFR inhibitors have been approved for clinical use, it is highly desirable to develop highly potent and selective EGFR inhibitors with novel scaffolds because of the occurrence of acquired resistance after treatment. Here we first demonstrate that the 4-indolyl quinazoline derivatives could potently inhibit EGFR in vitro and in vivo, of which YS-67 effectively and selectively inhibits EGFR[WT] (IC50 = 5.2 nM), EGFR[d746-750] (IC50 = 9.6 nM) and EGFR[L858R] (IC50 = 1.9 nM). The TREEspot™ kinase interaction map further reveals the binding selectivity toward 468 kinases. YS-67 not only potently suppresses p-EGFR and p-AKT, but also effectively inhibits proliferation of A549 (IC50 = 4.1 µM), PC-9 (IC50 = 0.5 µM) and A431 cells (IC50 = 2.1 µM). YS-67 treatment also causes colony formation inhibition, arrests cell cycle progression at G0/G1 phases and induces apoptosis. More importantly, YS-67 is well tolerated in A431 xenograft model after oral administration, showing effective tumor growth suppression and low toxicity. Collectively, YS-67 represents an underexplored scaffold for developing new EGFR inhibitors.
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Antineoplásicos , Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Quinazolinas , Neoplasias Pulmonares/tratamento farmacológico , Proliferação de Células , Inibidores de Proteínas Quinases , Linhagem Celular Tumoral , Receptores ErbB , MutaçãoRESUMO
Lysine-specific demethylase 1 (LSD1) has been identified as an important epigenetic target, and recent advances in lung cancer therapy have highlighted the importance of targeting ferroptosis. However, the precise mechanisms by which LSD1 regulates ferroptosis remain elusive. In this study, we report that the inhibition of LSD1 induces ferroptosis by enhancing lipid peroxidation and reactive oxygen species (ROS) accumulation. Mechanistically, LSD1 inhibition downregulates the expression of activating transcription factor 4 (ATF4) through epigenetic modification of histone H3 lysine 9 dimethyl (H3K9me2), which sequentially inhibits the expression of the cystine-glutamate antiporter (xCT) and decreases glutathione (GSH) production. Furthermore, LSD1 inhibition transcriptionally upregulates the expression of transferrin receptor (TFRC) and acyl-CoA synthetase long chain family member 4 (ACSL4) by enhancing the binding of histone H3 lysine 4 dimethyl (H3K4me2) to their promoter sequences. Importantly, the combination of an LSD1 inhibitor and a ferroptosis inducer demonstrates an enhanced anti-tumor effect in a xenograft model of non-small cell lung cancer (NSCLC), surpassing the efficacy of either agent alone. These findings reveal new insights into the mechanisms by which LSD1 inhibition induces ferroptosis, offering potential guidance for the development of new strategies in the treatment of NSCLC.
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Carcinoma Pulmonar de Células não Pequenas , Ferroptose , Neoplasias Pulmonares , Humanos , Histonas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Fator 4 Ativador da Transcrição/genética , Fator 4 Ativador da Transcrição/metabolismo , Lisina , Linhagem Celular Tumoral , Neoplasias Pulmonares/tratamento farmacológico , Histona Desmetilases/metabolismoRESUMO
The Epidermal Growth Factor Receptor (EGFR) tyrosine kinase inhibitors (TKIs) are the standard first-line therapy for EGFR-mutated NSCLC. However, long-term clinical treatment often leads to acquired drug resistance, making NSCLC refractory. Therefore, it is essential to design new EGFR inhibitors as potential drugs against NSCLC. This study reports on a novel quinazoline-based compound called YS-363 that acts as a new EGFR inhibitor. YS-363 demonstrated potent inhibition against both wild-type and L858R mutant forms of EGFR with IC50 values of 0.96 nM and 0.67 nM, respectively. Additionally, YS-363 had a reversible inhibitory effect on cellular EGFR signaling, had excellent inhibitory activity on cell proliferation and migration, and induced G0/G1 cell cycle arrest and apoptosis. In xenograft models dependent on EGFR signaling, oral administration of YS-363 substantially suppressed tumor growth by inhibiting this pathway. In summary, YS-363 is a promising selective reversible inhibitor with a novel quinazoline scaffold that can potentially develop more effective anti-lung cancer agents targeting EGFR in patients who have developed resistance to current therapies such as TKIs like gefitinib or erlotinib.
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AIM: Lysine-Specific Demethylase 1 (LSD1) inhibitors have been developed and reached the clinic, but its effect in combination with cytotoxic chemotherapy is unclear. Here, we investigated the anti-tumor effect of LSD1 inhibitor GSK-LSD1 and its anti-tumor effect with the DNA damage drug doxorubicin (DOX) in gastric cancer (GC) cells. METHODS: Cells were treated with different concentrations of GSK-LSD1 to examine the anti-tumor effect versus cell viability by MTT and cell cycle arrest by flow cytometry. To explore whether LSD1 inhibitors can increase the anti-tumor effect of DNA damage drugs, cells were treated with DOX for 48 h after pretreatment with GSK-LSD1 for 48 h. Cell viability was detected by MTT and apoptosis-related proteins were examined by Western blot. Furthermore, anti-tumor efficacy of combination GSK-LSD1 with DOX was also measured in MGC-803 xenografts model in nude mice. RESULTS: The results showed that LSD1 was highly expressed in GC cell lines. Inhibition of LSD1 has a weak effect on cell viability and cell cycle. Moreover, LSD1 inhibitors pretreatment could significantly increase the anti-tumor effect of DOX. Further study found that inhibition of LSD1 can significantly enhance DOX-induced the apoptosis, accompanied by down-regulation of antiapoptotic Bcl-2 expression and up-regulation of proapoptotic Bax expression. We also confirmed that inhibition of LSD1 can sensitize the anti-tumor effect of DOX in vivo. CONCLUSION: Our findings suggest that the LSD1 inhibitor GSK-LSD1 has a weak inhibitory effect on the viability and cell cycle of GC cells, but can enhance the sensitivity of DOX.
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Neoplasias Gástricas , Animais , Camundongos , Humanos , Neoplasias Gástricas/tratamento farmacológico , Lisina/farmacologia , Camundongos Nus , Doxorrubicina/farmacologia , Apoptose , Histona Desmetilases/metabolismo , Histona Desmetilases/farmacologia , Linhagem Celular Tumoral , Proliferação de CélulasRESUMO
This paper describes syntheses, photophysical properties, and electrochemical characteristics of three thieno[3,4-b]thiophene (TT)-based quinoidal oligomers OnTTO. The rigid planar backbones of these oligomers give the molecules narrow absorption bands, and the main absorption bands were significantly red-shifted when the TT units were extended and demonstrated wide transparent windows. The compound O4TTO was found to possess strong absorption in the near-infrared (NIR) region approaching 1200 nm but remained transparent in the visible region. Electrochemical experiments have shown that the energy band gaps gradually narrow when the TT units are increased. Optical properties predicted by density functional theory calculations are in good agreement with the experimental optical results. These dye molecules could be promising candidates for future NIR photodetectors, filters, and bioimaging technologies.
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The vitamin A metabolite all-trans retinoic acid (ATRA) plays a key role in immune response, but effects of ATRA on cancer-associated immunity remains unclear. Previously, we have shown that ATRA regulates the expression of PD-L1 in gastric cancer (GC) cells. We herein reported the mechanism underlying ATRA-induced PD-L1 expression in GC cells and the effects of ATRA on cancer-associated immunosuppression in vitro and in vivo. ATRA enhanced PD-L1 expression through increasing its protein stability and protein synthesis, which was suppressed by JAK pan-inhibitor ruxolitinib (RUX) but enhanced in the combination with IFN-γ. In T-cell-mediated killing assay, the upregulation of PD-L1-induced by ATRA rendered GC cells strongly resistant to activated T-cell killing, which was reversed by RUX. In vivo, PD-L1 antibody restricted tumor growth, but ATRA antagonized PD-L1 antibody efficacy. Importantly, RUX not only inhibited the expression of PD-L1 induced by ATRA, but also resensitized GC cells to PD-L1 antibody. In conclusion, our study illustrated that ATRA attenuated the effect of PD-L1 blockade through upregulating PD-L1 and blocking PD-L1 expression is an important role for the generation of effective anti-tumor immune response in the combination of immunotherapy and chemotherapy or targeted therapy.
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Antígeno B7-H1 , Neoplasias Gástricas , Antígeno B7-H1/metabolismo , Linhagem Celular Tumoral , Humanos , Imunoterapia , Neoplasias Gástricas/metabolismo , Linfócitos T , Tretinoína/farmacologia , Tretinoína/uso terapêuticoRESUMO
Targeting immune checkpoints such as programmed cell death protein 1 (PD-1) and programmed death ligand-1 (PD-L1) have been approved for treating melanoma, gastric cancer (GC) and bladder cancer with clinical benefit. Nevertheless, many patients failed to respond to anti-PD-1/PD-L1 treatment, so it is necessary to seek an alternative strategy for traditional PD-1/PD-L1 targeting immunotherapy. Here with the data from The Cancer Genome Atlas (TCGA) and our in-house tissue library, PD-L1 expression was found to be positively correlated with the expression of ubiquitin-specific processing protease 7 (USP7) in GC. Furthermore, USP7 directly interacted with PD-L1 in order to stabilize it, while abrogation of USP7 attenuated PD-L1/PD-1 interaction and sensitized cancer cells to T cell killing in vitro and in vivo. Besides, USP7 inhibitor suppressed GC cells proliferation by stabilizing P53 in vitro and in vivo. Collectively, our findings indicate that in addition to inhibiting cancer cells proliferation, USP7 inhibitor can also downregulate PD-L1 expression to enhance anti-tumor immune response simultaneously. Hence, these data posit USP7 inhibitor as an anti-proliferation agent as well as a novel therapeutic agent in PD-L1/PD-1 blockade strategy that can promote the immune response of the tumor.
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[This corrects the article DOI: 10.18632/oncotarget.2784.].
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AIMS: Programmed death ligand 1 (PD-L1, CD274) has been reported to be expressed abnormally in many cancers, nevertheless, effect of PD-L1 on tumor cells remains unclear, especially in gastric cancer (GC). This study aimed to investigate the role of PD-L1 in metastasis and differentiation in GC. MAIN METHODS: Immunohistochemistry was performed on 237 paired GC tissues. shPD-L1 cells were generated by lentivirus shRNA solution and PD-L1-overexpressing cells were constructed by pcDNA3.1. Expression of PD-L1 and E-cadherin in GC cells were detected by western blot. KEY FINDINGS: PD-L1 expression was significantly lower in GC than that in adjacent normal tissues, especially in poorly differentiated and metastatic GC, but was positively correlated to survival time of patients. Moreover, PD-L1 ablation could decrease E-cadherin expression, promote cell migration and wound repair ability. In turn, overexpression of PD-L1 increased E-cadherin expression and inhibited wound repair ability. At the same time, All-trans retinoic acid (ATRA), which has the properties of pro-differentiation and inhibition of invasion and metastasis, upregulated the expression of PD-L1 and E-cadherin. SIGNIFICANCE: These findings not only identify PD-L1 may have a positive role for the treatment of GC, but also implicate that ATRA combined PD-L1 antibody drugs may enhance anti-tumor Immunity in GC.
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Antígeno B7-H1/metabolismo , Neoplasias Gástricas/patologia , Antígeno B7-H1/fisiologia , Western Blotting , Caderinas/metabolismo , Linhagem Celular Tumoral , Técnicas de Silenciamento de Genes , Humanos , Neoplasias Gástricas/metabolismoRESUMO
EGFR tyrosine kinase inhibitor (EGFR-TKI) has been used successfully in clinic for the treatment of solid tumors. In the present study, we reported the discovery of WS-157 from our in-house diverse compound library, which was validated to be a potent and selective EGFR-TKI. WS-157 showed excellent inhibitory activities against EGFR (IC50 = 0.81 nmol/L), EGFR[d746-750] (IC50 = 1.2 nmol/L) and EGFR[L858R] (IC50 = 1.1 nmol/L), but was less effective or even inactive against other nine kinases. WS-157 also displayed excellent antiproliferative activities against a panel of human cancer cell lines, and exhibited the ability to reduce colony formation and wound healing the same as gefitinib. We found that WS-157 upon oral administration showed better anti-tumor activity in A431 bearing xenograft mouse models compared to gefitinib. In addition, WS-157 showed better intestinal absorption than gefitinib and had favorable pharmacokinetic properties and microsomal metabolic stability in different species. These studies indicate that WS-157 has strong antitumor activity in vitro and in vivo, and could be used for the development of anti-lung cancer agent targeting EGFR.
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Rationale: G9a is genetically deregulated in various tumor types and is important for cell proliferation; however, the mechanism underlying G9a-induced carcinogenesis, especially in colorectal cancer (CRC), is unclear. Here, we investigated if G9a exerts oncogenic effects in CRC by increasing polo-like kinase 1 (Plk1) expression. Thus, we further characterized the detailed molecular mechanisms. Methods: The role of Plk1 in G9a aberrant CRC was determined by performing different in vitro and in vivo assays, including assessment of cell growth by performing cell viability assay and assessment of signaling transduction profiles by performing immunoblotting, in the cases of pharmacological inhibition or short RNA interference-mediated suppression of G9a. Detailed molecular mechanisms underlying the effect of G9a on Plk1 expression were determined by performing point mutation analysis, chromatin immunoprecipitation analysis, and luciferase reporter assay. Correlation between G9a and Plk1 expression was determined by analyzing clinical samples of patients with CRC by performing immunohistochemistry. Results: Our study is the first to report a significant positive correlation between G9a and Plk1 levels in 89 clinical samples of patients with CRC. Moreover, G9a depletion decreased Plk1 expression and suppressed CRC cell growth both in vitro and in vivo, thus confirming the significant correlation between G9a and Plk1 levels. Further, we observed that G9a-induced Plk1 regulation depended on p53 inhibition. G9a dimethylated p53 at lysine 373, which in turn increased Plk1 expression and promoted CRC cell growth. Conclusions: These results indicate that G9a-induced and p53-dependent epigenetic programing stimulates the growth of colon cancer, which also suggests that G9a inhibitors that restore p53 activity are promising therapeutic agents for treating colon cancer, especially for CRC expressing wild-type p53.
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Carcinogênese/genética , Proteínas de Ciclo Celular/genética , Neoplasias Colorretais/metabolismo , Histona-Lisina N-Metiltransferase/metabolismo , Proteínas Serina-Treonina Quinases/genética , Proteínas Proto-Oncogênicas/genética , Proteína Supressora de Tumor p53/metabolismo , Animais , Carcinogênese/metabolismo , Proteínas de Ciclo Celular/metabolismo , Proliferação de Células , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Epigênese Genética , Células HCT116 , Células HEK293 , Células HT29 , Histona-Lisina N-Metiltransferase/genética , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Quinase 1 Polo-LikeRESUMO
G9a, a histone methyltransferase, is aberrantly expressed in some human tumor types. By comparing 182 paired colorectal cancer and peritumoral tissues, we found that G9a was highly expressed in colorectal cancer (CRC). Overexpression of G9a promoted CRC cells proliferation and colony formation, whereas knockdown of G9a inhibited CRC cells proliferation. Depletion of G9a increased the rate of chromosome aberration, induced DNA double strand breaks and CRC cells senescence. G9a inhibition synergistically increased γH2AX expression induced by topoisomerase I inhibitors and ultimately led to CRC cell death. The findings that down-regulation of G9a triggers DNA damage response and inhibits colorectal cancer cells proliferation may define G9a as potential oncotarget in CRC.
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Proliferação de Células , Neoplasias Colorretais/enzimologia , Dano ao DNA , Antígenos de Histocompatibilidade/metabolismo , Histona-Lisina N-Metiltransferase/metabolismo , Animais , Proliferação de Células/efeitos dos fármacos , Senescência Celular , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Regulação para Baixo , Regulação Enzimológica da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Técnicas de Silenciamento de Genes , Células HT29 , Antígenos de Histocompatibilidade/genética , Histona-Lisina N-Metiltransferase/genética , Histonas/metabolismo , Humanos , Camundongos Endogâmicos BALB C , Camundongos Nus , Interferência de RNA , Transdução de Sinais , Fatores de Tempo , Inibidores da Topoisomerase I/farmacologia , Transfecção , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
AIM: G226 is a novel derivative of epipolythiodioxopiperazines with potent inhibitory activity against cancer cells. Here, we sought to identify potential targets involved in the anti-cancer activity of G226. METHODS: Cell proliferation assay was conducted in a panel of 12 human cancer cell lines. The activities of topoisomerase I (Topo I) and Topo II were studied using supercoiled pBR322 DNA relaxation and kDNA decatenation assays. ROS production was assessed with probes DCFH-DA and H&E. Western blot analysis and flow cytometry were used to examine DNA damage, apoptosis and cell cycle changes. RESULTS: G226 displayed potent cytotoxicity in the 12 human cancer cell lines with a mean IC50 value of 92.7 nmol/L. This compound (1-100 µmol/L) selectively inhibited the activity of Topo II, and elevated the expression of phosphorylated-H2AX in a dose-dependent manner. In Topo II-deficient HL60/MX2 cells, however, G226-induced DNA damage, apoptosis and cytotoxicity were only partially reduced, suggesting that Topo II was not essential for the anti-tumor effects of G226. Furthermore, G226 (0.125-2 µmol/L) dose-dependently elevated the intracellular levels of H2O2 and in the cancer cells, and pretreatment with GSH, NAC or DTT not only blocked G226-induced intracellular accumulation of ROS, but also abrogated G226-mediated phosphorylation of H2AX, apoptosis and cytotoxicity. CONCLUSION: G226-mediated ROS production contributes to the anti-cancer activity of this compound.
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Apoptose/efeitos dos fármacos , Dano ao DNA , Dicetopiperazinas/farmacologia , Dissulfetos/farmacologia , Neoplasias/metabolismo , Neoplasias/patologia , Estresse Oxidativo/efeitos dos fármacos , Piperazinas/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Inibidores da Topoisomerase II/farmacologia , Antígenos de Neoplasias/genética , Antígenos de Neoplasias/metabolismo , Antioxidantes/farmacologia , Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , DNA Topoisomerases Tipo II/genética , DNA Topoisomerases Tipo II/metabolismo , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Relação Dose-Resposta a Droga , Células HCT116 , Células HL-60 , Células HT29 , Histonas/metabolismo , Humanos , Concentração Inibidora 50 , Neoplasias/genética , FosforilaçãoRESUMO
AIM: To investigate the effects of G226, a novel epipolythiodioxopiperazine derivative, on human breast cancer cells in vitro, and to explore its anticancer mechanisms. METHODS: A panel of human breast cancer cell lines (MDA-MB-231, MDA-MB-468, MCF-7, ZR-75-30, BT474, BT549, SK-BR-3, T47D and HBL100) was examined. Cell proliferation was measured using sulforhodamine B assay, and cell apoptosis was detected with flow cytometry and caspase activity assay. Western blotting, immunofluorescence and targeted gene knockdowns were used to study autophagy in the cells. RESULTS: G226 suppressed proliferation of the 9 breast cancer cell lines with a mean IC50 value of 48.5 nmol/L (the mean IC50 value of adriamycin, a reference compound, was 170.6 nmol/L). G226 induced dose-dependent apoptosis of MDA-MB-231 and MCF-7 cells, accompanied by markedly increased activities of caspase-8 and caspase-3/7, which were abolished by caspase inhibitors zVAD or zIETD. G226 also induced mitochondrial outer membrane permeabilization, resulted in the caspase-9 activation. Moreover, G226 dose-dependently enhanced the autophagy marker LC3-II and autophagy substrate p62 accumulation in the cells, which were co-localized with caspase-8. Silencing of p62 or LC3 partially diminished caspase-8 and subsequent caspase-3 activation. LC3 silencing partially reversed G226-induced apoptosis, but p62 silencing elicited a subtle effect on G226-induced apoptosis. CONCLUSION: The novel epipolythiodioxopiperazine derivative G226 exerts potent anticancer action against human breast cancer cells in vitro, via triggering autophagy and caspase-dependent apoptosis.