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Ferroptosis is a newly characterized form of regulated cell death mediated by iron-dependent accumulation of lipid reactive oxygen species and holds great potential for cancer therapy. However, the molecular mechanisms underlying ferroptosis remain largely elusive. In this study, we define an integrative role of DJ-1 in ferroptosis. Inhibition of DJ-1 potently enhances the sensitivity of tumor cells to ferroptosis inducers both in vitro and in vivo. Metabolic analysis and metabolite rescue assay reveal that DJ-1 depletion inhibits the transsulfuration pathway by disrupting the formation of the S-adenosyl homocysteine hydrolase tetramer and impairing its activity. Consequently, more ferroptosis is induced when homocysteine generation is decreased, which might be the only source of glutathione biosynthesis when cystine uptake is blocked. Thus, our findings show that DJ-1 determines the response of cancer cells to ferroptosis, and highlight a candidate therapeutic target to potentially improve the effect of ferroptosis-based antitumor therapy. DJ-1 protects cells from oxidative stress-induced cell death; however its role in ferroptosis is unclear. Here, the authors show that DJ-1 suppresses ferroptosis through the transsulfuration pathway to compensate for the depletion of intracellular cysteine when cystine import is inhibited. [ABSTRACT FROM AUTHOR]

Metastasis-associated drug resistance accounts for high mortality in ovarian cancer and remains to be a major barrier for effective treatment. In this study, SKOV3/T4, a metastatic subpopulation of ovarian cancer SKOV3 cells, was enriched to explore potential interventions against metastatic-associated drug resistance. Quantitative genomic and functional analyses were performed and found that slug was significantly increased in the SKOV3/T4 subpopulation and contributed to the high resistance of SKOV3/T4. Further studies showed that slug activated c-Met in a ligand-independent manner due to elevated levels of fibronectin and provoked integrin α V function, which was confirmed by the significant correlation of slug and p-Met levels in 121 ovarian cancer patient samples. Intriguingly, c-Met inhibitor(s) exhibited greatly enhanced anti-cancer effects in slug-positive ovarian cancer models both in vitro and in vivo. Additionally, IHC analyses revealed that slug levels were highly correlated with reduced survival of ovarian cancer patients. Taken together, this study not only uncovers the critical roles of slug in drug resistance in ovarian cancer but also highlights a promising therapeutic strategy by targeting the noncanonical activation of c-Met in slug-positive ovarian cancer patients with poor prognosis. In order to overcome chemotherapy resistance in metastatic ovarian cancer patients, we enriched a metastatic subpopulation of SKOV3 cells to explore the mechanisms underlying metastatic-associated drug resistance. Quantitative genomic and functional analyses uncover the critical roles of slug in metastatic-associated drug resistance, which can be overcome by c-Met inhibitor(s) both in vitro and in vivo. The finding also presents a new exciting opportunity to overcome metastatic-associated drug resistance for ovarian cancer patients by targeting c-Met signaling, particularly those patients harboring high expression levels of Slug and poor prognosis. fx1 [ABSTRACT FROM AUTHOR]

Background: Chemotherapy is the only therapy option for the majority of AML patients, however, there are several limitations for this treatment. Our aim was to find a new chemotherapy strategy that is more effective and less toxic. Methods: MTT assays and a xenograft mouse model were employed to evaluate the synergistic activity of all-trans retinoic acid (ATRA) combined with topotecan (TPT). Drug-induced DNA damage and apoptosis were determined by flow cytometry analysis with PI and DAPI staining, the comet assay and Western blots. Short hairpin RNA (shRNA) and a RARα plasmid were used to determine whether RARα expression influenced DNA damage and apoptosis. Results: We found that ATRA exhibited synergistic activity in combination with Topotecan in AML cells, and the enhanced apoptosis induced by Topotecan plus ATRA resulted from caspase pathway activation. Mechanistically, ATRA dramatically down regulated RARα protein levels and led to more DNA damage and ultimately resulted in the synergism of these two agents. In addition, the increased antitumor efficacy of Topotecan combined with ATRA was further validated in the HL60 xenograft mouse model. Conclusions: Our data demonstrated, for the first time, that the combination of TPT and ATRA showed potential benefits in AML, providing a novel insight into clinical treatment strategies. [ABSTRACT FROM AUTHOR]

Abstract: A series of 2,4-diarylchromane[4,3-d]-Δ1,9b-1,2,3-thiadiazolines have been synthesized by cyclization of corresponding 2-arylchroman-4-one-arylhydrazones with SOCl2 then treated with alcohol. All the compounds have been tested for their antiproliferative activity in vitro against six human tumor cell lines, and the highly potent derivative 11a exhibited in vivo inhibitory effect on tumor growth. Mechanism research indicated that it is due to 11a that induces DNA fragmentation. [Copyright &y& Elsevier]

Pancreatic ductal adenocarcinoma (PDAC) is characterized by abundant cancer-associated fibroblasts (CAFs), early perineural invasion (PNI) and microvascular invasion (MVI). However, the differentiation trajectories and underlying molecular mechanisms of CAFs in PDAC early invasion have not been fully elucidated. In this study, we integrated and reanalysed single-cell data from the National Geoscience Data Centre (NGDC) database and confirmed that myofibroblast-like CAFs (myCAFs) mediated epithelial-mesenchymal transformation (EMT) and enhanced the invasion abilities of PDAC cells by secreting regulators of angiogenesis and metastasis. Furthermore, we constructed a differentiation trajectory of CAFs and revealed that reprogramming from iCAFs to myCAFs was associated with poor prognosis. Mechanistically, SOX4 was aberrantly activated in myCAFs, which promoted the secretion of MMP11 and eventually induced early cancer cell invasion. Together, our results provide a comprehensive transcriptomic overview of PDAC patients with early invasion and reveal the intercellular crosstalk between myCAFs and cancer cells, which suggests potential targets for early invasion PDAC therapy. [Display omitted] • myCAFs enhances metastatic capacity of PDAC cells via secreting various regulators. • The reprogramming from iCAFs to myCAFs is associated with poor prognosis. • SOX4 is aberrantly activated in myCAFs and promotes secretion of MMP11. • SOX4+ myCAFs is a potential therapeutic target of metastatic PDAC. [ABSTRACT FROM AUTHOR]

Epigenetic dysregulation plays a crucial role in the development and progression of ovarian cancer. Since the first experiment conducted on resistant ovarian cancer cells using demethylating drugs, multiple clinical trials have revealed that epigenetic targeted drugs combined with chemotherapy, molecular-targeted drugs, or even immunotherapy could enhance tumor sensitivity and reverse acquired resistances. Here, we summarized the combination strategies of epigenetic targeted drugs with other treatment strategies of ovarian cancer and discussed the principles of combination therapy. Finally, we enumerated several reasonable clinical trial designs as well as future drug development strategies, which may provide promising ideas for the application of epigenetic drugs to ovarian cancer. Drug resistance is pervasive in ovarian cancer treatment and needs improved treatment strategies. Nowadays, it's promising to combine with epigenetic targeted drugs, which are potentially being investigated and explored. [Display omitted] [ABSTRACT FROM AUTHOR]

Hypoxia-inducible factor 1 (HIF-1), a heterodimeric transcription factor that mediates the adaptation of tumor cells and tissues to the hypoxic microenvironment, has attracted considerable interest as a potential therapeutic target. Recently, HIF-1α has been recognized as the critical target of cardiac glycosides for cancer therapy, but the molecular mechanism of cardiac glycosides’ inhibition of HIF-1α is still poorly understood. In the present study, we observed that neither HIF-1α mRNA levels nor HIF-1α protein degradation are affected by Ouabain. However, Ouabain was found to be associated with the regulation of HIF-1α translation. Basing on in silico, in vitro and ex vivo models of translation processing, further studies revealed that eIF4E plays a critical role in the inhibitory effect of Ouabain on HIF-1α protein synthesis, rather than mTORC1, eIF2α signaling or Na+/K+-ATPase inhibition. Mechanistically, Ouabain directly binds eIF4E, disrupts eIF4E/eIF4G association (200μM, Inhibit rate =61±3%) but not the eIF4E/mRNA complex formation (200μM, Inhibit rate =18±5%) both in vitro and in cells, thereby inhibiting the intracellular cap-dependent translation. The association between Ouabain and eIF4E not only raises the hope of using cardiac glycosides for cancer therapeutics more rational, but also offers a pharmacologic means for developing novel anti-cancer HIF-1α antagonists. [ABSTRACT FROM AUTHOR]

Abstract: Combretastatin A-4 (CA-4) has already entered clinical trials of solid tumors over ten years. However, the limited anticancer activity and dose-dependent toxicity restrict its clinical application. Here, we offered convincing evidence that CA-4 induced autophagy in various cancer cells, which was demonstrated by acridine orange staining of intracellular acidic vesicles, the degradation of p62, the conversion of LC3-I to LC3-II and GFP-LC3 punctate fluorescence. Interestingly, CA-4-mediated apoptotic cell death was further potentiated by pretreatment with autophagy inhibitors (3-methyladenine and bafilomycin A1) or small interfering RNAs against the autophagic genes (Atg5 and Beclin 1). The enhanced anticancer activity of CA-4 and 3-MA was further confirmed in the SGC-7901 xenograft tumor model. These findings suggested that CA-4-elicited autophagic response played a protective role that impeded the eventual cell death while autophagy inhibition was expected to improve chemotherapeutic efficacy of CA-4. Meanwhile, CA-4 treatment led to phosphorylation/activation of JNK and JNK-dependent phosphorylation of Bcl-2. Importantly, JNK inhibitor or JNK siRNA inhibited autophagy but promoted CA-4-induced apoptosis, indicating a key requirement of JNK-Bcl-2 pathway in the activation of autophagy by CA-4. We also identified that pretreatment of Bcl-2 inhibitor (ABT-737) could significantly enhance anticancer activity of CA-4 due to inhibition of autophagy. Taken together, our data suggested that the JNK-Bcl-2 pathway was considered as the critical regulator of CA-4-induced protective autophagy and a potential drug target for chemotherapeutic combination. [Copyright &y& Elsevier]

Abstract: A series of novel 2-aliphatic cyclic amine-3-(arylsulfonyl)quinoxalines was synthesized based on the structural features of a previously identified lead, WR1. The 2-piperidinol-3-(arylsulfonyl)quinoxalines, which showed excellent antitumor activities against five human cell lines, with inhibitory activities ranging from 0.34 to 2.32μM, proved to be a promising class of novel PI3Kα inhibitors. The most potent compound 10d (WR23) showed an inhibitory IC50 value of 0.025μM against PI3Kα and significant pAkt suppression effect. Molecular docking analysis was performed to determine possible binding modes between PI3Kα and target compounds. [Copyright &y& Elsevier]

Abstract: A series of novel 2-arylamino-3-(arylsulfonyl)quinoxalines was synthesized through a newly developed approach. All synthesized target compounds were screened for their cytotoxicities against cancer cell lines including PC3, A549, HCT116, HL60 and KB. Representative compounds with favorable cytotoxicities were tested for their PI3Kα inhibitory activities. Among the synthesized target compounds, 17 (PI3Kα IC50: 0.07 μM) displayed the most potent cellular activities (IC50 values of 0.14 μM, 0.07 μM, 0.95 μM and 0.05 μM against PC3, A549, HCT116 and HL 60, respectively). [Copyright &y& Elsevier]

Abstract: A series of new 4β-anilino-4′-O-demethyl-4-desoxypodophyllotoxin derivatives were prepared and evaluated for their cytotoxicities against four human cancer cell lines including KB, KB/VCR, A549 and 95D. Most compounds showed better growth-inhibition activities against tested cell lines than that of etoposide (VP-16). Preliminary structure–activity relationships (SARs) were concluded and it indicated that the side chains substituted at 4β position of podophyllotoxin significantly influenced the cytotoxic activity, especially for the drug resistance profile. In vivo studies of compound 26c on highly metastatic human lung cancer xenograft in nude mice showed that it can significantly inhibit tumor growth with administrating by oral route. [Copyright &y& Elsevier]

Abstract: Akt signaling pathway has attracted much attention as a promising target for cancer therapeutics. Herein, we report that Isobavachalcone (IBC), a natural chalcone, potently abrogates Akt signaling and exerts anti-proliferative effects on several human cancer cell lines. Modeling results from the Sybyl/FlexiDock program suggest that IBC potentially binds to the ATP-binding pocket of Akt, which is confirmed by the observations that IBC inhibits Akt1 kinase in vitro. Further studies reveal that IBC significantly abates Akt phosphorylation at Ser-473 and Akt kinase activity in cells, which subsequently leads to inhibition of Akt downstream substrates and evokes significant levels of apoptosis associated with mitochondria pathway. [Copyright &y& Elsevier]

Abstract: The present data showed that sunitinib potentiated the in vitro and in vivo anticancer capabilities of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), also known as Apo2 ligand. Interactions between sunitinib and TRAIL were examined in colon cancer SW620 cells and lung cancer 95-D cells. The average combination index (CI) values of the anti-proliferation abilities on each cancer cell line were less than 1.0, demonstrating the synergism of the combination of sunitinib and TRAIL. Western blot experiments indicated that TRAIL and sunitinib synergistically enhanced apoptosis by simultaneously activating the extrinsic and intrinsic pathways. The decrease in the expression levels of anti-apoptotic proteins cFLIP, XIAP and Mcl-1 were probably involved in this apoptosis enhancement. Furthermore, treatment of colon cancer SW620-bearing nude mice with sunitinib plus TRAIL resulted in more significant tumor growth inhibition (52.8%), comparing with the moderate inhibition in TRAIL-treated (35.3%) or sunitinib-treated groups (26.7%) (p <0.05). These results indicate that the combination of TRAIL with sunitinib seems highly encouraging and warrants further investigation in a clinical setting. [Copyright &y& Elsevier]

Abstract: The present data showed that a novel synthesized compound, N-acetyl-N-(4-(4-methoxyphenyl-3-(3,4,5-trimethoxyphenyl)isoxazol-5-yl)acetamide (XN05), exhibited potent antitumor activity against various cancer cells in vitro. XN05-treatment in human hepatocellular carcinoma cells resulted in the accumulation of G2/M phase cells and finally induced apoptosis assessed by flow cytometry analysis. Western blot and immunofluorescence experiments indicated that XN05 depolymerized microtubules similar to the effect of combretastatin-A4. In addition, XN05-treatment influenced the expression of cell cycle and apoptosis related proteins in BEL-7402 cells, which was associated with the appearance of phosphorylated Bcl-2. Taken together, all the data demonstrated that XN05 exhibited its antitumor activity through disrupting the microtubule assembly, causing cell cycle arrest and consequently inducing apoptosis in BEL-7402 cells. Therefore, the novel compound XN05 is a promising microtubule inhibitor that has great potentials for therapeutic treatment of various malignancies. [Copyright &y& Elsevier]

Abstract: A series of cis-restricted 3,4-diaryl-5-aminoisoxazoles have been synthesized and evaluated for their biological activities. Among them, compound 11a and 13a displayed potent cytotoxic activities in vitro against five human cancer cell lines with IC50 values in the low micromolar range and two compounds inhibited tubulin polymerization with IC50 value of 1.8, and 2.1μM, respectively, similar to that of CA-4. Compound 13a could arrest at the G2/M phase of the cell cycle at the concentration of 0.1 and 1.0μM and induce apoptosis at 0.1–1.0μM. [Copyright &y& Elsevier]

Abstract: A series of novel 7-azaindazolyl-indolyl-maleimides were synthesized and evaluated for their antiproliferative activity in vitro against various human cancer cell lines and protein kinase C inhibitory activity. Compounds 8a–c, 8e and 14a were the most promising compounds against K562, A549, ECA-109, KB and SMMC-7721 cell lines in vitro. Compounds 9a–j showed moderate PKC inhibition. Further mechanism of action studies revealed that the antiproliferative activity of compound 8b in KB cells might involve the mitochondria-mediated apoptosis pathway. [Copyright &y& Elsevier]

Abstract: Three series of γ-carboline derivatives were designed and synthesized. All the compounds were tested for their cytotoxic activities in vitro against five human tumor cell lines (A549, SGC, HCT116, MCF-7, K562) and one multi-drug resistant subline (K562R). Most compounds showed moderate to potent cytotoxic activities against the tested cell lines. Sulfonate 11f exhibited more potent cytotoxic activities against almost all of the tested cells in comparison with the positive control, taxol, with IC50 values ranging from 0.15 to 4.5μM. The structure–activity relationships were discussed and a statistically reliable QSAR model (r 2 =0.936, q 2 =0.581) was established by the CoMFA analysis performed using the cytotoxic data against K562 cell line as a template. [Copyright &y& Elsevier]

Abstract: A new series of aryl substituted imidazol-2-one derivatives structurally related to combretastatin A-4 (CA-4) were synthesized and evaluated for their cytotoxic activities in vitro against various human cancer cell lines including MDR cell line. The cytotoxic effects of compounds 7b and 7i proved to be similar to or greater than that of docetaxel. The highly active compound 7b also exhibited excellent inhibitory activity on tumor growth in vivo. [Copyright &y& Elsevier]

Thioredoxin 1 (Trx1) and telomerase play key roles in the development and progression process of most tumors, and they both are promising drug therapy targets. We have, for the first time, discovered that Trx1 and telomerase had a dual-target synergistic effect. Based on that results, we designed a series of 6-dithio-2′-deoxyguanosine analogs (named as YLS00X) and verified whether they can inhibit Trx1 and telomerase simultaneously. TrxR1/Trx1 system activity and telomerase expression were significantly inhibited by 6-dithio-2′-deoxyguanosine analogs, especially YLS004. YLS004 can also cause ROS accumulation, and induce tumor cell apoptosis. The vitro antitumor activity of 6-dithio-2′-deoxyguanosine analogs using MTT assay on 11 different human cancer cells and found that human colon cancer cells(HCT116) and melanoma cells (A375) were the most sensitive cells to 6-dithio-2′-deoxyguanosine analogs treatment and vivo xenografts models also confirmed that. The serum biochemical parameters and multiple organs HE staining results of subacute experiments indicated that YLS004 might be mildly toxic to immune organs, including the thymus, spleen, and hematopoietic system. Besides, YLS004 was rapidly metabolized in the rats' blood. Our study revealed that YLS004, a Trx1 and telomerase inhibitor, has strong anti-tumor effects to colon cancer and melanoma cells and is a promising new candidate drug. Unlabelled Image • Trx1 and telomerase have a dual-target synergistic effect. • YLS00X can inhibit Trx1 and telomerase simultaneously. • YLS00X cause ROS accumulation and induce colon cancer and melanoma cells apoptosis. [ABSTRACT FROM AUTHOR]