Induce Cancer Cell Research Articles

Kaempferol and its derivatives: Biological activities and therapeutic potential

Kaempferol, a natural plant-origin flavonoid, exhibits therapeutic anti-inflammatory, antioxidant, anticancer, antidiabetic, and neuroprotective properties. Kaempferol acts within several distinct mechanisms like apoptotic induction in cancer cells, enzymatic inhibition, signalling pathway inhibition, and downregulation in cell viability during the G2/M phase of cell division. This review summarizes the therapeutic effects of kaempferol against several health ailments. The recent progress on kaempferol obtained from fruits and vegetables as an antioxidant, anti-inflammatory, anticancer, antidiabetic, and neuroprotective agent and its mechanisms of action are also discussed. In addition, kaempferol has been reported to be present in wastes and byproducts from post-fruit and vegetable processing. Thus, a paradigm shift towards valorizing fruits and vegetable industrial wastes/byproducts to obtain bioactive kaempferol can support the circular economy pillar for generating wealth from waste and for finding a sustainable alternative source.

The tumor suppressive effect and apoptotic mechanism of TRAIL gene-containing recombinant NDV in TRAIL-resistant colorectal cancer HT-29 cells and TRAIL-nonresistant HCT116 cells, with each cell bearing a mouse model.

TRAIL is an anticancer drug that induces cancer cell apoptosis by interacting with death receptors (DRs). However, owing to low cell-surface expression of DRs, certain colorectal cancer (CRC) cells resist TRAIL-induced apoptosis. Newcastle disease virus (NDV) infection can elevate DR protein expression in cancer cells, potentially influencing their TRAIL sensitivity. However, the precise mechanism by which NDV infection modulates DR expression and impacts TRAIL sensitivity in cancer cells remains unknown. Herein, we developed nonpathogenic NDV VG/GA strain-based recombinant NDV (rNDV) and TRAIL gene-containing rNDV (rNDV-TRAIL). We observed that viral infections lead to increased DR and TRAIL expressions and activate signaling proteins involved in intrinsic and extrinsic apoptosis pathways. Experiments were conducted invitro using TRAIL-resistant CRC cells (HT-29) and nonresistant CRC cells (HCT116) and invivo using relevant mouse models. rNDV-TRAIL was found to exhibit better apoptotic efficacy than rNDV in CRC cells. Notably, rNDV-TRAIL had the stronger cancer cell-killing effect in TRAIL-resistant CRC cells. Western blot analyses showed that both rNDV and rNDV-TRAIL infections activate signaling proteins involved in the intrinsic and extrinsic apoptotic pathways. Notably, rNDV-TRAIL promotes concurrent intrinsic and extrinsic signal transduction in both HCT-116 and HT-29 cells. Therefore, rNDV-TRAIL infection effectively enhances DR expression in DR-depressed HT-29 cells. Moreover, the TRAIL protein expressed by rNDV-TRAIL effectively interacts with DR, leading to enhanced apoptosis in TRAIL-resistant HT-29 cells. Therefore, rNDV-TRAIL has potential as a promising therapeutic approach for treating TRAIL-resistant cancers.

Up-Regulation of TCF21 Expression Reverses the Malignant Phenotype of Cancer-Associated Fibroblasts in Esophageal Squamous Cell Carcinoma

Cancer-associated fibroblasts (CAFs), as one major component of tumor microenvironment (TME), are closely associated with tumor initiation and progression. Our previous studies have discovered that CAFs induced the resistance of esophageal squamous cell carcinoma (ESCC) cells to a variety of chemotherapeutic drugs such as cisplatin and paclitaxel. Furthermore, CAFs attenuated ionizing irradiation (IR)-induced cancer cells death by regulating DNA damage response. CAFs themselves are highly resistant to death stimuli due to enhanced antioxidant potential and DNA repair capacity. How to inhibit the malignant phenotype of CAFs is critically important for the radical treatment of ESCC. By RNA-sequencing and DNA methylation analysis, the transcriptome and epigenome of CAFs and matched normal fibroblasts (NFs) have been integratively analyzed. By transfection of TCF21 cDNA plasmid, the expression of TCF21 in CAFs has been up-regulated. Using a cell counting kit and migration and invasion assay, the effect of TCF21 on the growth and migration and invasive ability of CAFs has been detected. Using immunofluorescence and flow cytometry (FCM) analysis and western blotting, the effect of TCF21 on the DNA damage repair and apoptotic death of CAFs following IR has been detected. TCF21 is one of the top ten down-regulated genes in CAFs compared with NFs due to promoter methylation. Up-regulation of TCF21 expression inhibited the growth rate and migration and invasive ability of CAFs. The expression of α-SMA, as an indicator of CAFs activation, was down-regulated in CAFs which were transfected with TCF21 cDNA. Furthermore, when TCF21 cDNA was transfected into CAFs, IR-induced DNA damage was increased while DNA repair was inhibited in CAFs, suggesting that TCF21 was involved in DNA damage response of CAFs following IR. FCM analysis showed that up-regulation of TCF21 expression promoted IR-induced apoptotic death of CAFs. TCF21 is a determinant of the malignant phenotype of CAFs in ESCC. Up-regulation of TCF21 expression is a promising approach of inhibiting the growth, migration and invasion, activation and radioresistance of CAFs in ESCC.

Vitamin C Improves the Inhibitory Effects of Oxaliplatin on HCT-116 Colorectal Cancer Growth and Progression Through Cellular Oxidant Function-associated Cadherin Molecules.

Colorectal cancer (CRC) is strongly associated with altered cadherin adhesion molecules. Oxaliplatin is a standard treatment for CRC, yet high-doses have concerning side effects. In this study, the effects of oxaliplatin and the combination of oxaliplatin with vitamin C on HCT-116 CRC cell migration and invasion were studied through the roles of cellular oxidative stress associated with cadherin molecules. The cellular assays used in this research were MTT, DCFH-DA, immunofluorescence, and western blotting. Cancer progression was examined using wound healing and Boyden chamber techniques. The results indicate that hydrogen peroxide-induced cellular oxidative stress induced cancer cell migration and invasion. The combined treatment of oxaliplatin with a pro-oxidant concentration of vitamin C resulted in higher toxicity than treatment with oxaliplatin alone. However, treatment with the combination of oxaliplatin and antioxidant concentrations of vitamin C suppressed cancer migration and invasion. Furthermore, the combination treatment increased E-cadherin expression, whereas decreased that of N-cadherin. Treatment with the combination of oxaliplatin with vitamin C can inhibit CRC cell growth and decrease cancer cell migration and invasion, via oxidative stress and cadherins.

Anti-cancer effects of the bioactive compounds of Prunus dulcis against ovarian cancer cell lines (PA-1)

The use of natural substances in cancer treatment is the current need because alternative approaches are intensive and have numerous negative side effects. In this current study, the natural product Prunus dulcis (Almond) was screened for its ability to inhibit the proliferation of (PA-1) cancer cells. In the MTT assay, IC50 values obtained are 220 μg/ml. Reactive Oxygen Species (ROS), Mitochondrial Membrane Potential (MMP) and Apoptosis induction in cancer cells of the ovary are noticed and this assay shows the anti-cancerous activity of Prunus dulcis. Catechin has emerged as the major bioactive compound of Prunus dulcis. Anti-bacterial activity of Prunus dulcis at various concentrations of 50, 80, 90 and 100μl was tested. 90μl of Prunus dulcis extract showed a good antibacterial effect against Saccharomyces cerevisiae. This research shows that the almond bioactive molecules inhibit the proliferation of ovarian cancer cell lines. The identified promising active pharmaceutical ingredient catechin needs focused research.

Peptide-Appended Nanosonosensitizers Targeting Tumor Glycolysis for Synergistic Sonodynamic-Immunometabolic Therapy of Spinal-Metastasized Tumors.

Despite recent advancements in cancer immunotherapy, challenges have yet to be surmounted to achieve two major goals of magnifying antitumor immunity and remodeling the immunosuppressive tumor microenvironment. Here, a nanosystem (ODM-R) that integrates oxygen-deficient molybdenum oxide (ODM) nanosonosensitizers and R7 peptides with tumor metabolism regulation effects is designed and fabricated for synergistic sonodynamic-immunometabolic therapy of spinal-metastasized tumors. The ODM generates reactive oxygen species upon ultrasound irradiation to implement sonodynamic therapy (SDT), inducing cancer cell apoptosis and immunogenic cell death. The R7 attached on ODM markedly inhibits the uptake of glucose and excretion of lactic acid in cancer cells by perturbing the glycolysis process. The combination of SDT and tumor glycolysis obstruction by ODM-R guarantees satisfactory efficacy in synergizing with PD-L1 antibody to eradicate spinal-metastasized tumors, achieving concurrent sonodynamic-triggered immune activation and immunosuppressive tumor microenvironment remodeling. This work provides a proof-of-concept of nanosonosensitizers for boosting cancer immunotherapy by SDT and tumor metabolic regulation.

Cyclometalated Ir(III) Complexes as Lysosome-Targeted Photodynamic Anticancer Agents.

We have designed and synthesized two Ir(III) complexes (Ir1 and Ir2) coordinated with an 8-sulfonamidoquinoline derivative ligand as photosensitizers, which exhibit strong red phosphorescence emission and a long phosphorescence lifetime. The Ir(III) complexes exhibit a high population of triplet states, which enable red phosphorescence and efficient singlet oxygen generation. Ir1 and Ir2 rapidly enter the cancer cells and accumulate in lysosomes, producing large amounts of intracellular singlet oxygen when exposed to light irradiation, eventually leading to cancer cell death, and the phototoxic indexes of complexes Ir1 and Ir2 against cancer cells are in the range of 76-228. Overall, our studies indicate that the synthesized Ir(III) complexes with quinoline ligands exhibit photosensitizing properties, effectively inducing cancer cell death when exposed to light. These promising results suggest their potential application in photodynamic therapy.

Commentary on: The actin bundling activity of ITPKA mainly accounts for its migration-promoting effect in lung cancer cells.

1,4,5-triphosphate 3-kinase A (ITPKA) was first described and characterized by Irvine et al. in 1986 and cloned by Takazawa et al. in 1990. It is one of the components of the Ca2+ and calmodulin signaling pathway and a substrate for cAMP-dependent kinase (PKA) and protein kinase C (PKC), and is mainly involved in the regulation of intracellular inositol polyphosphate signaling molecules. Through a series of studies, Sabine's team has found that ITPKA expression was up-regulated in a variety of cancer cells, and silencing ITPKA inhibited while overexpressing ITPKA promoted cancer cell migration in vitro and metastasis in vivo. The latest research from Sabine's team has demonstrated that in H1299 lung cancer cells, the mechanism by which ITPKA promoted migration and invasion was predominantly depending on the ability of binding to F-actin, which will induce cancer cells to form a tight flexible actin networks. Small molecule compounds targeting the IP3 kinase activity of ITPKA protein may only inhibit the migration and invasion of cancer cells caused by the enhanced ITPKA kinase activity under ATP stimulation, but not the cytoskeletal remodeling caused by the binding of ITPKA protein to F-actin and the driven migration and invasion of cancer cells. Therefore, targeted therapeutic strategy focusing on blocking the binding of ITPKA to F-actin is indispensable when designing the inhibitors targeting ITPKA protein.

Possible Mechanisms of Dark Tea in Cancer Prevention and Management: A Comprehensive Review.

Tea is one of the most popular drinks in the world. Dark tea is a kind of post-fermented tea with unique sensory characteristics that is produced by the special fermentation of microorganisms. It contains many bioactive substances, such as tea polyphenols, theabrownin, tea polysaccharides, etc., which have been reported to be beneficial to human health. This paper reviewed the latest research on dark tea's potential in preventing and managing cancer, and the mechanisms mainly involved anti-oxidation, anti-inflammation, inhibiting cancer cell proliferation, inducing cancer cell apoptosis, inhibiting tumor metastasis, and regulating intestinal flora. The purpose of this review is to accumulate evidence on the anti-cancer effects of dark tea, the corresponding mechanisms and limitations of dark tea for cancer prevention and management, the future prospects, and demanding questions about dark tea's possible contributions as an anti-cancer adjuvant.

Single-atom nanozymes based nanobee vehicle for autophagy inhibition-enhanced synergistic cancer therapy

Single-atom nanozymes (SAzyme) have shown great promise in the area of anti-tumor therapy due to their ultra-high atom utilization efficiency. However, the therapeutic effect is far from satisfactory because of cunning cancer cell's self-protective autophagy. Herein, to solve this dilemma, we design a large-pore mesoporous Fe SAzyme loaded with macromolecular melittin pro-peptide to form Fe SAzyme@melittin pro-peptide (FePM) nanobee. When the FePM enter cells through endocytosis and are entrapped in endo/lysosomes, Fe SAzyme with glutathione oxidase (GSHOx), peroxidase (POD) and oxidase (OXD) mimicking activities can trigger collaborative CDT and ferroptosis by provoking a GSH depletion-enhanced ROS storm. Additionally, the strong absorption ability in the near-infrared II region endows Fe SAzyme with excellent PTT performance (42.1%). More importantly, the non-toxic melittin pro-peptide can be activated to membrane-lytic active melittin by overexpressed legumain in the lysosomes of cancer cells. Activated melittin then disrupts lysosomes, in this case inhibiting autophagy by reducing the formation of autolysosomes. Therefore, FePM nanobee can effectively damage cytoplasmic components to induce cancer cells death by synergistic ferroptosis, CDT and PTT. This study sheds light on the first example of large-pore mesoporous SAzyme for autophagy inhibition-enhanced multimodal synergistic antitumor therapy.

Design, synthesis, and antitumor screening of new thiazole, thiazolopyrimidine, and thiazolotriazine derivatives as potent inhibitors of VEGFR-2.

New thiazole, thiazolopyrimidine, and thiazolotriazine derivatives 3-12 and 14a-f were synthesized. The newly synthesized analogs were tested for in vitro antitumor activity against HepG2, HCT-116, MCF-7, HeP-2, and Hela cancer cells. Results indicated that compound 5 displayed the highest potency toward the tested cancer cells. Compound 11b possessed enhanced effectiveness over MCF-7, HepG2, HCT-116, and Hela cancer cells. In addition, compounds 4 and 6 showed promising activity toward HCT-116, MCF-7, and Hela cancer cells and eminent activity against HepG2 and HeP-2 cells. Moreover, compounds 3-6 and 11b were tested for their capability to inhibit vascular endothelial growth factor receptor-2(VEGFR-2) activity. The obtained results showed that compound 5 displayed significant inhibitory activity against VEGFR-2 (half-maximal inhibitory concentration[IC50 ] = 0.044 μM) comparable to sunitinib (IC50 = 0.100 μM). Also, the synthesized compounds 3-6 and 11b were subjected to in vitro cytotoxicity tests over WI38 and WISH normal cells. It was found that the five tested compounds displayed significantly lower cytotoxicity than doxorubicin toward normal cell lines. Cell cycle analysis proved that compound 5 induces cell cycle arrest in the S phase for HCT-116 and Hela cancer cell linesand in the G2/M phase for theMCF-7 cancer cell line. Moreover, compound 5 induced cancer cell death through apoptosis accompanied by a high ratio of BAX/BCL-2 in the screened cancer cells. Furthermore, docking results revealedthat compound 5 showedthe essential interactionbonds with VEGFR-2, which agreed with in vitro enzyme assay results. In silico studies showed that most of the analyzed compounds complied with the requirements of good oral bioavailability with minimal toxicity threats in humans.

Converting bacteria into autologous tumor vaccine via surface biomineralization of calcium carbonate for enhanced immunotherapy

Autologous cancer vaccine that stimulates tumor-specific immune responses for personalized immunotherapy holds great potential for tumor therapy. However, its efficacy is still suboptimal due to the immunosuppressive tumor microenvironment (ITM). Here, we report a new type of bacteria-based autologous cancer vaccine by employing calcium carbonate (CaCO3) biomineralized Salmonella (Sal) as an in-situ cancer vaccine producer and systematical ITM regulator. CaCO3 can be facilely coated on the Sal surface with calcium ionophore A23187 co-loading, and such biomineralization did not affect the bioactivities of the bacteria. Upon intratumoral accumulation, the CaCO3 shell was decomposed at an acidic microenvironment to attenuate tumor acidity, accompanied by the release of Sal and Ca2+/A23187. Specifically, Sal served as a cancer vaccine producer by inducing cancer cells' immunogenic cell death (ICD) and promoting the gap junction formation between tumor cells and dendritic cells (DCs) to promote antigen presentation. Ca2+, on the other hand, was internalized into various types of immune cells with the aid of A23187 and synergized with Sal to systematically regulate the immune system, including DCs maturation, macrophages polarization, and T cells activation. As a result, such bio-vaccine achieved remarkable efficacy against both primary and metastatic tumors by eliciting potent anti-tumor immunity with full biocompatibility. This work demonstrated the potential of bioengineered bacteria as bio-active vaccines for enhanced tumor immunotherapy.

TERT accelerates BRAF mutant-induced thyroid cancer dedifferentiation and progression by regulating ribosome biogenesis.

TERT reactivation occurs frequently in human malignancies, especially advanced cancers. However, in vivo functions of TERT reactivation in cancer progression and the underlying mechanism are not fully understood. In this study, we expressed TERT and/or active BRAF (BRAF V600E) specifically in mouse thyroid epithelium. While BRAF V600E alone induced papillary thyroid cancer (PTC), coexpression of BRAF V600E and TERT resulted in poorly differentiated thyroid carcinoma (PDTC). Spatial transcriptome analysis revealed that tumors from mice coexpressing BRAF V600E and TERT were highly heterogeneous, and cell dedifferentiation was positively correlated with ribosomal biogenesis. Mechanistically, TERT boosted ribosomal RNA (rRNA) expression and protein synthesis by interacting with multiple proteins involved in ribosomal biogenesis. Furthermore, we found that CX-5461, an rRNA transcription inhibitor, effectively blocked proliferation and induced redifferentiation of thyroid cancer. Thus, TERT promotes thyroid cancer progression by inducing cancer cell dedifferentiation, and ribosome inhibition represents a potential strategy to treat TERT-reactivated cancers.

Characterisation of laminarin extracted from brown seaweed Laminaria digitata, using optimized ultrasound- and ultrafiltration-assisted extraction method

The present study reported the extraction and characterisation of laminarin from Laminaria digitata. Hydrochloric acid concentration and extraction time were investigated by central composite design for optimizing extraction conditions. Regarding purification of the supernatant after the extraction process, membrane ultrafiltration was selected over pH shifting, ethanol precipitation and freeze-drying. With the assistance of ultrasound technology in the extraction process, the highest laminarin extraction yield and purity were obtained up to 57.34 ± 1.58 % and 81.10 ± 0.37 %, respectively. The molecular weight of laminarin extracts is in the range of 5.61 to 5.95 kDa. The Fourier-transform infrared spectroscopy (FT-IR) spectral features of the averaged spectra were depicted as absorbance peaks at the wavelengths of 3340 cm−1 and 2922 cm−1, which were related to OH and CH stretching of laminarin. US probe extract showed the highest scavenging capacity of 52.96 % while the HCl conventional extract exhibited the lowest scavenging capacity of 30.82 %. All the optimized laminarin extracts showed higher cytotoxicity in A549, A431, and Caco-2 carcinomas, effectively inducing cancer cell death in a time- and dose-dependent manner, and lower cytotoxicity in BEAS-2B normal human bronchial epithelial cells when compared to commercial laminarin.

Catalytic Signal Transduction Theory Enabled Virtual Screening of Nanomaterials for Medical Functions.

ConspectusDeveloping biocompatible catalytic nanomaterials (NMs) to target cancer reactive oxygen species (ROS) has provided an alternative chemotherapy strategy for cancer. Compared to the traditional chemotherapy strategy, this catalytic NM-based strategy can take advantage of the nanoscale and catalytic effects of materials and thus is promising to conquer the troubles from which traditional strategies usually suffer, e.g., high dosage, low targeting, severe toxicity and side effects, and susceptibility to drug resistance. Therefore, the corresponding research has been one of the hottest topics in the frontier interdisciplinary field combining materials, chemistry, biology, and medicine. So far, many NMs have been reported to have potential in cancer catalytic therapy. Despite the progress, the chemicobiological mechanisms and principles, which underlie ROS-targeted catalysis and subsequent cancer therapeutic functions of NMs have remained elusive. Therefore, although numerous inorganic NMs have been synthesized with their structural information deposited in publicly available databases, it is still challenging to computationally design or screen the appropriate candidates with the desired medical functions from the libraries.In this Account, catalytic signal transduction theory has been proposed to bridge the gap between the knowledge of catalytic activities and medical functions of inorganic NMs. The atomistic-level mechanisms responsible for the activities of inorganic NMs in catalyzing cellular ROS conversions, namely, H2O2 activation, H2O2 dismutation, O2 activation, and O2•- dismutation, have been studied by density functional theory calculations. On the basis of the mechanisms, the kinetic equations and prediction models for some of the catalyses have been developed, making it possible to systematically and quantitatively describe the relationships between the surface structures and catalytic activities of NMs. The catalytic signal transduction theory assumes that the catalytic activities of NMs dominate their therapeutic activities in cancer catalytic therapy and that the order of catalytic activities mainly determines the order of therapeutic activities for NMs of the same series. According to this theory, the prediction models have been implemented into computer programs with the aid of machine learning to realize high-throughput computational screening of candidate NMs toward cancer catalytic therapy.The results have revealed mechanisms and rules on how inorganic NMs induce cancer cell death by catalyzing the chemical conversions of cellular ROS. They provided theoretical tools for the in silico design and screening of candidate NMs for cancer therapy. To make catalytic signal transduction a general approach of tuning life with catalytic NMs, the challenge now remains to achieve substrate selectivity for catalytic NMs and a systematic and deep understanding of their interactions with entire biosystems.

TRIM21-Promoted FSP1 Plasma Membrane Translocation Confers Ferroptosis Resistance in Human Cancers.

Ferroptosis, an iron-dependent form of regulated cell death driven by excessive accumulation of lipid peroxides, has become a promising strategy in cancer treatment. Cancer cells exploit antioxidant proteins, including Ferroptosis Suppressor Protein 1 (FSP1), to prevent ferroptosis. In this study, it is found that the E3 ubiquitin ligase TRIM21 bound to FSP1 and mediated its ubiquitination on K322 and K366 residues via K63 linkage, which is essential for its membrane translocation and ferroptosis suppression ability. It is further verified the protective role of the TRIM21-FSP1 axis in RSL3-induced ferroptosis in cancer cells and a subcutaneous tumor model. Moreover, TRIM21 is highly expressed in multiple gastrointestinal (GI) tumors, and its expression is further stimulated upon ferroptosis induction in cancer cells and the KPC mouse model. In summary, This study identifies TRIM21 as a negative regulator of ferroptosis through K63 ubiquitination of FSP1, which can serve as a therapeutic target to enhance the chemosensitivity of tumors based on ferroptosis induction.

Inhibition of USP2 Enhances TRAIL-Mediated Cancer Cell Death through Downregulation of Survivin.

Ubiquitin-specific protease 2 (USP2) is a deubiquitinase belonging to the USPs subfamily. USP2 has been known to display various biological effects including tumorigenesis and inflammation. Therefore, we aimed to examine the sensitization effect of USP2 in TRAIL-mediated apoptosis. The pharmacological inhibitor (ML364) and siRNA targeting USP2 enhanced TNF-related apoptosis-inducing ligand (TRAIL)-induced cancer cell death, but not normal cells. Mechanistically, USP2 interacted with survivin, and ML364 degraded survivin protein expression by increasing the ubiquitination of survivin. Overexpression of survivin or USP2 significantly prevented apoptosis through cotreatment with ML364 and TRAIL, whereas a knockdown of USP2 increased sensitivity to TRAIL. Taken together, our data suggested that ML364 ubiquitylates and degrades survivin, thereby increasing the reactivity to TRAIL-mediated apoptosis in cancer cells.

Melatonin as a regulator of apoptosis in leukaemia: molecular mechanism and therapeutic perspectives.

Leukaemia is a dangerous malignancy that causes thousands of deaths every year throughout the world. The rate of morbidity and mortality is significant despite many advancements in therapy strategies for affected individuals. Most antitumour medications used now in clinical oncology use apoptotic signalling pathways to induce cancer cell death. Accumulated data have shown a direct correlation between inducing apoptosis in cancer cells with higher tumour regression and survival. Until now, the efficacy of melatonin as a powerful antitumour agent has been firmly established. A change in melatonin concentrations has been reported in multiple tumours such as endometrial, hematopoietic, and breast cancers. Findings show that melatonin's anticancer properties, such as its prooxidation function and ability to promote apoptosis, indicate the possibility of utilizing this natural substance as a promising agent in innovative cancer therapy approaches. Melatonin stimulates cell apoptosis via the regulation of many apoptosis facilitators, including mitochondria, cytochrome c, Bcl-2, production of reactive oxygen species, and apoptosis receptors. This paper aimed to further assess the anticancer effects of melatonin through the apoptotic pathway, considering the role that cellular apoptosis plays in the pathogenesis of cancer. The effect of melatonin may mean that it is appropriate for use as an adjuvant, along with other therapeutic approaches such as radiotherapy and chemotherapy.

Gut microbiota-derived short-chain fatty acids promote prostate cancer progression via inducing cancer cell autophagy and M2 macrophage polarization

We have previously demonstrated abnormal gut microbial composition in castration-resistant prostate cancer (CRPC) patients, here we revealed the mechanism of gut microbiota-derived short-chain fatty acids (SCFAs) as a mediator linking CRPC microbiota dysbiosis and prostate cancer (PCa) progression. By using transgenic TRAMP mouse model, PCa patient samples, in vitro PCa cell transwell and macrophage recruitment assays, we examined the effects of CRPC fecal microbiota transplantation (FMT) and SCFAs on PCa progression. Our results showed that FMT with CRPC patients’ fecal suspension increased SCFAs-producing gut microbiotas such as Ruminococcus, Alistipes, Phascolarctobaterium in TRAMP mice, and correspondingly raised their gut SCFAs (acetate and butyrate) levels. CRPC FMT or SCFAs supplementation significantly accelerated mice's PCa progression. In vitro, SCFAs enhanced PCa cells migration and invasion by inducing TLR3-triggered autophagy that further activated NF-κB and MAPK signalings. Meanwhile, autophagy of PCa cells released higher level of chemokine CCL20 that could reprogramme the tumor microenvironment by recruiting more macrophage infiltration and simultaneously polarizing them into M2 type, which in turn further strengthened PCa cells invasiveness. Finally in a cohort of 362 PCa patients, we demonstrated that CCL20 expression in prostate tissue was positively correlated with Gleason grade, pre-operative PSA, neural/seminal vesical invasion, and was negatively correlated with post-operative biochemical recurrence-free survival. Collectively, CRPC gut microbiota-derived SCFAs promoted PCa progression via inducing cancer cell autophagy and M2 macrophage polarization. CCL20 could become a biomarker for prediction of prognosis in PCa patients. Intervention of SCFAs-producing microbiotas may be a useful strategy in manipulation of CRPC.

Mesoporous polydopamine nanoplatforms loaded with calcium ascorbate for amplified oxidation and photothermal combination cancer therapy

AbstractDestruction of cellular redox homeostasis to induce cancer cell apoptosis is an emerging tumor therapeutic strategy. To achieve this goal, elevating exogenous oxidative stress or impairing the antioxidant defense system of cancer cells is an effective method. Herein, we firstly report a biocompatible and versatile nanoplatform based on mesoporous polydopamine (MpDA) nanoparticles and a phase‐change material (PCM) for delivering calcium ascorbate (Vc‐Ca), simultaneously enabling combination therapy of hyperthermia, reactive oxygen species (ROS) generation, and suppression of tumor antioxidant capability. In this design, Vc‐Ca encapsulated in MpDA using PCM is controllably released due to the melting of PCM matrix in response to photothermal heating upon near‐infrared irradiation. Vc‐Ca is proved to be a pro‐oxidant that can promote the production of ROS (H2O2) in the tumor site. Remarkably, MpDA can not only act as a photothermal agent but also can break the redox balance of cancer cells through depleting the primary antioxidant glutathione, thus amplifying Vc‐Ca‐mediated oxidative therapy. Both in vitro and in vivo results demonstrate the significantly enhanced antitumor activity of boosted ROS combined with local hyperthermia. This study highlights the potential applications of Vc‐Ca in cancer treatment, and the prepared multifunctional nanoplatform provides a novel paradigm for high‐efficiency oxidation‐photothermal therapy.