Isocitrate dehydrogenase-1 (Idh1) is an important metabolic enzyme that produces NADPH by converting isocitrate to alpha -ketoglutarate. Idh1 is known to reduce reactive oxygen species (ROS) induced ...in cells by treatment with lipopolysaccharide (LPS) in vitro. Here, we used Idh1-deficient knockout (Idh1 KO) mice to investigate the role of Idh1 in antioxidant defense in vivo. Idh1 KO mice showed heightened susceptibility to death induced by LPS and exhibited increased serum levels of inflammatory cytokines such as tumor necrosis factor- alpha and interleukin-6. The serum of LPS-injected Idh1 KO mice also contained elevated levels of AST, a marker of inflammatory liver damage. Furthermore, after LPS injection, livers of Idh1 KO mice showed histological evidence of elevated oxidative DNA damage compared with livers of wild-type (WT) mice. Idh1 KO livers showed a faster and more pronounced oxidative stress than WT livers. In line with that, Idh1 KO hepatocytes showed higher ROS levels and an increase in the NADP super(+)/NADPH ratio when compared with hepatocytes isolated from WT mice. These results suggest that Idh1 has a physiological function in protecting cells from oxidative stress by regulating the intracellular NADP super(+)/NADPH ratio. Our findings suggest that stimulation of Idh1 activity may be an effective therapeutic strategy for reducing oxidative stress during inflammatory responses, including the early stages of septic shock.
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DOBA, EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, IZUM, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UILJ, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Cancer cells have higher reactive oxygen species (ROS) than normal cells, due to genetic and metabolic alterations. An emerging scenario is that cancer cells increase ROS to activate protumorigenic ...signaling while activating antioxidant pathways to maintain redox homeostasis. Here we show that, in basal-like and BRCA1-related breast cancer (BC), ROS levels correlate with the expression and activity of the transcription factor aryl hydrocarbon receptor (AhR). Mechanistically, ROS triggers AhR nuclear accumulation and activation to promote the transcription of both antioxidant enzymes and the epidermal growth factor receptor (EGFR) ligand, amphiregulin (AREG). In a mouse model of BRCA1-related BC, cancer-associated AhR and AREG control tumor growth and production of chemokines to attract monocytes and activate proangiogenic function of macrophages in the tumor microenvironment. Interestingly, the expression of these chemokines as well as infiltration of monocyte-lineage cells (monocyte and macrophages) positively correlated with ROS levels in basal-like BC. These data support the existence of a coordinated link between cancer-intrinsic ROS regulation and the features of tumor microenvironment. Therapeutically, chemical inhibition of AhR activity sensitizes human BC models to Erlotinib, a selective EGFR tyrosine kinase inhibitor, suggesting a promising combinatorial anticancer effect of AhR and EGFR pathway inhibition. Thus, AhR represents an attractive target to inhibit redox homeostasis and modulate the tumor promoting microenvironment of basal-like and BRCA1-associated BC.
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BFBNIB, NMLJ, NUK, PNG, SAZU, UL, UM, UPUK
Triple-negative breast cancer (TNBC) is the most aggressive breast cancer subtype with the worst prognosis and few effective therapies. Here we identified MS023, an inhibitor of type I protein ...arginine methyltransferases (PRMTs), which has antitumor growth activity in TNBC. Pathway analysis of TNBC cell lines indicates that the activation of interferon responses before and after MS023 treatment is a functional biomarker and determinant of response, and these observations extend to a panel of human-derived organoids. Inhibition of type I PRMT triggers an interferon response through the antiviral defense pathway with the induction of double-stranded RNA, which is derived, at least in part, from inverted repeat Alu elements. Together, our results represent a shift in understanding the antitumor mechanism of type I PRMT inhibitors and provide a rationale and biomarker approach for the clinical development of type I PRMT inhibitors.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Tumorigenesis results from dysregulation of oncogenes and tumor suppressors that influence cellular proliferation, differentiation, apoptosis, and/or senescence. Many gene products involved in these ...processes are substrates of the E3 ubiquitin ligase Mule/Huwe1/Arf-BP1 (Mule), but whether Mule acts as an oncogene or tumor suppressor in vivo remains controversial. We generated K14Cre;Mule(flox/flox(y)) (Mule kKO) mice and subjected them to DMBA/PMA-induced skin carcinogenesis, which depends on oncogenic Ras signaling. Mule deficiency resulted in increased penetrance, number, and severity of skin tumors, which could be reversed by concomitant genetic knockout of c-Myc but not by knockout of p53 or p19Arf. Notably, in the absence of Mule, c-Myc/Miz1 transcriptional complexes accumulated, and levels of p21CDKN1A (p21) and p15INK4B (p15) were down-regulated. In vitro, Mule-deficient primary keratinocytes exhibited increased proliferation that could be reversed by Miz1 knockdown. Transfer of Mule-deficient transformed cells to nude mice resulted in enhanced tumor growth that again could be abrogated by Miz1 knockdown. Our data demonstrate in vivo that Mule suppresses Ras-mediated tumorigenesis by preventing an accumulation of c-Myc/Miz1 complexes that mediates p21 and p15 down-regulation.
Many 3D in vitro models induce breast cancer spheroid formation; however, this alone does not recapitulate the complex in vivo phenotype. To effectively screen therapeutics, it is urgently needed to ...validate in vitro cancer spheroid models against the gold standard of xenografts. A new oxime‐crosslinked hyaluronan (HA) hydrogel is designed, manipulating gelation rate and mechanical properties to grow breast cancer spheroids in 3D. This HA‐oxime breast cancer model maintains the gene expression profile most similar to that of tumor xenografts based on a pan‐cancer gene expression profile (comprising 730 genes) of three different human breast cancer subtypes compared to Matrigel or conventional 2D culture. Differences in gene expression between breast cancer cultures in HA‐oxime versus Matrigel or 2D are confirmed for 12 canonical pathways by gene set variation analysis. Importantly, drug response is dependent on the culture method. Breast cancer cells respond better to the Rac inhibitor (EHT‐1864) and the PI3K inhibitor (AZD6482) when cultured in HA‐oxime versus Matrigel. This study demonstrates the superiority of an HA‐based hydrogel as a platform for in vitro breast cancer culture of both primary, patient‐derived cells and cell lines, and provides a hydrogel culture model that closely matches that in vivo.
The first oxime‐crosslinked hyaluronan‐based hydrogel is synthesized as a platform for in vitro 3D culture of both primary, patient‐derived breast cancer cells and cell lines. The superiority of this system over other common strategies relative to in vivo models is demonstrated, thereby providing an in vitro biomimetic system for use in drug screening and personalized medicine.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
The therapeutic value of repeat hepatic resection (rHR) or radiofrequency ablation (RFA) for recurrent hepatocellular carcinoma (HCC) is unknown. This study aimed to investigate the safety and ...efficacy of rHR or RFA.
This was a retrospective multicentre study of patients with recurrent HCC within the Milan criteria who underwent rHR or RFA at nine university hospitals in China and Italy between January 2003 and January 2018. Survival after rHR or RFA was examined in unadjusted analyses and after propensity score matching (1 : 1).
Of 847 patients included, 307 and 540 underwent rHR and RFA respectively. Median overall survival was 73.5 and 67.0 months after rHR and RFA respectively (hazard ratio 1.01 (95 per cent c.i. 0.81 to 1.26)). Median recurrence-free survival was longer after rHR versus RFA (23.6 versus 15.2 months; hazard ratio 0.76 (95 per cent c.i. 0.65 to 0.89)). These results were confirmed after propensity score matching. RFA was associated with lower morbidity of grade 3 and above (0.6 versus 6.2 per cent; P < 0.001) and shorter hospital stay (8.0 versus 3.0 days, P < 0.001) than rHR.
rHR was associated with longer recurrence-free survival but not overall survival compared with RFA.
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BFBNIB, FZAB, GIS, IJS, KILJ, NUK, OILJ, SBCE, SBMB, UL, UPUK
G-quadruplex DNAs form four-stranded helical structures and are proposed to play key roles in different cellular processes. Targeting G-quadruplex DNAs for cancer treatment is a very promising ...prospect. Here, we show that CX-5461 is a G-quadruplex stabilizer, with specific toxicity against BRCA deficiencies in cancer cells and polyclonal patient-derived xenograft models, including tumours resistant to PARP inhibition. Exposure to CX-5461, and its related drug CX-3543, blocks replication forks and induces ssDNA gaps or breaks. The BRCA and NHEJ pathways are required for the repair of CX-5461 and CX-3543-induced DNA damage and failure to do so leads to lethality. These data strengthen the concept of G4 targeting as a therapeutic approach, specifically for targeting HR and NHEJ deficient cancers and other tumours deficient for DNA damage repair. CX-5461 is now in advanced phase I clinical trial for patients with BRCA1/2 deficient tumours (Canadian trial, NCT02719977, opened May 2016).
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Microtubule-targeting agents are important tools in cancer treatment. Generating novel microtubule targeting agents with novel pharmacology could dramatically expand the utility of ...this class of drugs. Here we characterize the pharmacology of recently described small molecule microtubule polymerization inhibitors. Pharmacokinetic experiments show oral bioavailability through gastric absorption. In vitro assays designed to predict absorption, distribution, metabolism, and excretion (ADME) and safety reveal a scaffold that is metabolically stable, evades P-glycoprotein, does not inhibit CYP enzymes, occurs as a significant free fraction in serum, and has exceptionally high cellular permeability. Together with in vivo efficacy models, pharmacology supports further development as a treatment for solid tumors.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Neoadjuvant chemotherapy (NAC) is standard of care for locally advanced breast cancer. There is wide variation in radiation therapy (RT) practice and limited data describing locoregional relapse ...(LRR) after NAC. We hypothesized a low LRR risk with modern NAC, surgery, and RT and aimed to elucidate patterns of LRR and predictors of disease-free survival (DFS) and overall survival (OS) in these patients.
Data from 416 patients with stage II/III breast cancer treated between 2008 and 2015 with NAC, surgery, and adjuvant RT were reviewed retrospectively. DFS and OS rates were calculated using the Kaplan-Meier method. The LRR rate was estimated using the cumulative incidence function, treating death as a competing risk. Multivariable survival analysis was performed using Cox regression.
Median follow-up was 4.7 years. Most patients had cT2/3 (74%) cN1 (61%) disease and underwent mastectomy (75%) and axillary dissection (84%). Pathologic complete response (pCR) was achieved in 22% of patients. There were 27 LRRs (including 4 isolated LRRs) and 89 distant failures. Two patients developed LRR 2 months after surgery, before adjuvant RT. LRR could be mapped in 23 patients: most (20) recurred within the RT field; 1 in- and out-of-field; and 2 out-of-field. Five-year LRR, DFS, and OS were 6.4%, 77%, and 90%, respectively. On multivariable analysis, triple-negative subtype (hazard ratio HR 2.82; 95% confidence interval CI, 1.78-4.47; P < .001), stage III disease (HR 1.72; 95% CI, 1.11-2.69; P = .016), and non-pCR (HR 4.76; 95% CI 2.13-10.0; P < .001) were associated with poor DFS and OS (HR 4.13 95% CI, 2.21-7.72; P < .001; HR 1.94 95% CI, 1.001-3.75; P = .049; and HR 2.38 95% CI, 0.98-5.88; P = .055, respectively).
Patients with breast cancer treated with modern NAC, surgery, and RT have a low 5-year LRR risk, with the majority occurring in-field. Triple-negative subtype, stage III disease, and non-pCR were associated with inferior DFS and OS.
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