Inhibit Cancer Progression Research Articles

Overexpression of Bromodomain and Extraterminal Domain is Associated with Progression, Metastasis and Unfavorable Outcomes: Highlighting Prognostic and Therapeutic Value of the BET Protein Family in Gastric Cancer.

As epigenetic readers, Bromodomain and extraterminal domain (BET) proteins have attracted immense interest in developing novel therapies targeting this family to inhibit cancer progression. Although the impact of BRD4 in the carcinogenesis of various tumors has been widely investigated, little is known about the potential roles of the BET family in gastric cancer. In this cohort study, we have screened the expression profile of the BET protein family, including three members, BRD2, BRD3 and BRD4, in fresh gastric cancer (GC), adjacent non-tumor and normal gastric tissues, as well as the anti-cancer effects and molecular mechanisms of BET inhibition in GC cell lines. Among GC patients, BRD2, BRD3 and BRD4 showed overexpression, 48.07% (25/52), 61.5% (32/52) and 63.46% (33/52), respectively. The overexpression of BRD3 and BRD4 were remarkably associated with unfavorable outcomes (HR = 2.023, P = 0.038; HR = 3.874, P = 0.001, respectively). However, multivariate Cox regression analysis indicated that BRDs mRNA expression could not be used as an independent prognostic factor for GC patients after adjustment with other variables. I-BET151, a potent pan-inhibitor, suppressing the BET family, decreased cell growth, migration and invasion of GC cells. Interestingly, I-BET151 induced G1 cell cycle arrest through down-regulation of c-Myc and its target, CDK2/Cyclin D1 complex. Our data provide insights into the prognostic role of the BET family in GC and proposed BET inhibition as a therapeutic strategy for GC patients.

MSCs and CAFs interactions in the prostate and bladder cancer microenvironment as the potential cause of tumour progression

The tumour microenvironment (TME) is the broadly understood environment around the tumour. Cancer-associated fibroblasts (CAFs), Mesenchymal Stromal Cells (MSCs), and molecules synthesized by them are part of it. Both CAFs and MSCs can promote tumour progression by induction of an immunosuppressive, pro-inflammatory environment. Through indirect and direct cell-to-cell interactions they also have a pro-proliferative, pro-angiogenic, and pro-invasive effect on cancer cells. They can lead to aggressive cancer formation. At this stage, it is important to conduct research to modulate TME towards inhibition of cancer progression and preventing resistance to already introduced drugs. Moreover, it is extremely important to study these interactions in light of using MSCs in a drug-delivery strategy.

The effects of the prognostic biomarker SAAL1 on cancer growth and its association with the immune microenvironment in lung adenocarcinoma

BackgroundInhibition of Serum Amyloid A-like 1 (SAAL1) expression could inhibit cancer progression and improve the prognosis of cancer patients. At present, the correlation between SAAL1 and lung adenocarcinoma (LAC) remains unclear. Therefore, this study surveyed the worth and pathway of SAAL1 in LAC progression and immunity.MethodsBioinformatics and immunohistochemistry were used to identify the SAAL1 expression in LAC. The roles of SAAL1 expression in the existence values of LAC patients were explored, and the nomograms were constructed. Clinical values of SAAL1 co-expressed genes were evaluated by COX regression, survival, and Receiver operating characteristic (ROC) analysis. EDU and western blotting methods were used to inquiry the functions and pathways of the SAAL1 in cell growths. The correlation between the SAAL1 level and immune microenvironment was visualized using correlation research.ResultsSAAL1 level was elevated in LAC tissues, and was observed in cancer tissues of dead patients. SAAL1 overexpression had something to do with shorter overall survival, progression-free interval, and disease-specific survival in LAC. The area under the curve of SAAL1 was 0.902 in normal tissues and cancer tissues. Inhibition of SAAL1 expression could inhibit cancer cell proliferation, which may be related to the decreased expression of cyclin D1 and Bcl-2 proteins. In LAC, SAAL1 level had something to do with stromal, immune, and estimate scores, and correlated with macrophages, T cells, Th2 cells, CD8 T cells, NK CD56dim cells, DC, eosinophils, NK CD56bright cells, pDC, iDC, cytotoxic cells, Tgd, aDC cells, B cells, Tcm, and TFH levels. SAAL1 overexpression had something to do with existence values and the immunity in LAC.ConclusionsInhibition of SAAL1 expression could regulate cancer growth via cyclin D1 and Bcl-2. SAAL1 is a promising prognostic biomarker in LAC patients.

Exosome-derived miRNAs regulate macrophage-colorectal cancer cell cross-talk during aggressive tumor development

Colorectal cancer is one of the leading causes of death worldwide. Its incidence and mortality have significantly increased during the past few years. Colorectal cancer cells cross-talk with other cells through exosomes in their tumor microenvironment. The miRNAs containing exosomes are responsible for tumor growth, invasion, and metastasis. Multiple studies have shown that exosomal miRNAs are key players in the crosstalk between cancerous, immune, and stromal cells during colorectal cancer development. They help in the establishment of the tumorigenic microenvironment by reprogramming macrophages towards a pro-tumorigenic phenotype. In this review, we discussed various exosomal miRNAs derived both from colorectal cancer cells and macrophages that promote or inhibit cancer aggression. We also discussed various miRNA-based therapeutic approaches to inhibit cancer progression.

Do Certain Anaesthetic Drugs Affect Postoperative Cancer Recurrence Rates? Implications for Drug Discovery

Recurrence of cancer after primary tumour resection is a leading cause of cancer-related mortality. Preclinical research indicates that surgery induces a stress response that inhibits cell-mediated immunity as a possible basis for risk of recurrence. Other preclinical evidence suggests that, conversely, propofol and local anaesthetics diminish the effects of the surgical stress response and so could directly inhibit cancer progression, and this is supported by several retrospective cohort studies and meta-analyses. However, the first large-scale randomised clinical trial (RCT), comparing recurrence after mastectomy in patients anaesthetised with either propofol/local anaesthetic or sevoflurane/opioids, concluded that recurrence was not significantly improved in the propofol/local anaesthetic group (p = 0.84). Other cancers may prove more responsive and results from a number of ongoing RCTs, encompassing several cancer types, are currently awaited. These trials should establish whether choice of anaesthetic technique is an important determinant of cancer recurrence risk.

Abstract P3-07-19: Anti-depressant Amitriptyline Augments the Efficacy of Tamoxifen in ER positive breast cancer

Abstract Anti-depressant Amitriptyline Augments the Efficacy of Tamoxifen in ER positive breast cancer Pitta Venkata Prabhakar1, Arhan D Rao1, Timilsina Santosh1, Deepika Singh1, Ratna Vadlamudi1,2, Virginia Kaklamani3, Manjeet Rao1,2. 1Greehey Children’s Cancer Research Institute, University of Texas Health San Antonio, San Antonio, TX, USA. 2Mays Cancer Center, University of Texas Health San Antonio, San Antonio, TX, USA. 3Department of Medicine, UT Health, San Antonio, USA. Background: Breast cancer (BC) is the most common cancer in women and the leading cause of cancer-related deaths in women worldwide, with 1 out of 8 women being diagnosed with invasive breast cancer during their lifetime. The majority of breast cancer patients (80%) are diagnosed with Estrogen Receptor positive (ER+) breast cancer. The most commonly used treatment option for ER+ Breast cancer is endocrine therapy, such as Tamoxifen(TAM). Although survival of breast cancer patients has dramatically improved with the use of endocrine therapy, acquired resistance and debilitating side effects of treatment became major concerns. Therefore, safer treatment options that effectively suppress cancer progression, reduce treatment associated side effects, and improve efficacy of standard of care therapies are much needed. Repurposing of clinically approved or investigational drugs has become promising alternative approach for treating cancer. Therefore, we tested the repurposing potential of anti-depressant Amitriptyline for the treatment of ER+ breast cancer. Methods: The anti-cancer effect of Amitriptyline was determined in vitro using short and long-term viability, migration, and apoptosis assays. To substantiate the in vitro data, the effect of Amitriptyline on tumor growth was assessed using orthotopic xenograft model. RNA-seq analysis was performed in Vehicle and Amitriptyline treated breast cancer cells to understand the mechanism of action. Finally, to test whether amitriptyline can sensitize ER+ breast cancer cells to endocrine therapy, we performed cell viability assays after treatment with Amitriptyline and Tamoxifen. Results: Amitriptyline treatment resulted in significant reduction of short term and long term viability, as well as, migration of ER+ BC cells. Furthermore, Amitriptyline treatment significantly increased apoptosis in BC cells. Our RNA-seq analysis revealed that Amitriptyline treatment inhibited important genes involved in cancer growth and survival including E2F signaling, G2/M pathway, and DNA repair pathways. Confirming our in vitro findings, Amitriptyline treatment blocked the growth of ER+ BC growth in pre-clinical orthotopic xenograft model of breast cancer. Importantly, Amitriptyline treatment sensitized ER+ BC to TAM, showing highly synergistic effects. Amitriptyline treatment significantly improved the effects of TAM on cell viability, survival, migration, and apoptosis. Furthermore, Amitriptyline augmented the efficacy of Tamoxifen in TAM resistant BC cells. Conclusion: Our study establishes potential of Amitriptyline as a repurposable drug as safe and robust treatment option for ER+ patients, either as a monotherapy or in combination. We are poised to begin a clinical trial and test the therapeutic efficacy of Amitriptyline for treating breast cancer patients. Citation Format: Prabhakar Pitta Venkata, Arhan D. Rao, Santosh Timilsina, Deepika Singh, Ratna K. Vadlamudi, Virginia Kaklamani, Manjeet K. Rao. Anti-depressant Amitriptyline Augments the Efficacy of Tamoxifen in ER positive breast cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P3-07-19.

LncRNA TRG-AS1 inhibits bone metastasis of breast cancer by the miR-877-5p/WISP2 axis.

TRG-AS1 has been proved to inhibit cancer progression, whereas its effect on bone metastases of breast cancer is unknown. In this study, we determined breast cancer patients with disease free survival is longer in breast cancer patients with high TRG-AS1 expression. Moreover, TRG-AS1 was downregulated in breast cancer tissues and even lower in bone metastatic tumor tissues. Compared with parental breast cancer cell MDA-MB-231, TRG-AS1 expression was downregulated in MDA-MB-231-BO cells with strong bone-metastatic characteristics. Next, the binding sites of miR-877-5p on TRG-AS1 and WISP2 mRNA were predicted and result showed that miR-877-5p could bind to 3'UTR of TRG-AS1 and WISP2. Subsequently, BMMs and MC3T3-E1 cells were cultured in the conditioned media of MDA-MB-231 BO cells transfected with TRG-AS1 overexpression vector, shRNA and/or miR-877-5p mimics or inhibitor and/or overexpression vector and small interfering RNA of WISP2. TRG-AS1 silencing or miR-877-5p overexpression promoted MDA-MB-231 BO cell proliferation and invasion. TRG-AS1 overexpressing reduced TRAP positive cells, decreased TRAP, Cathepsin K, c-Fos, NFATc1 and AREG expression in BMMs, and promoted OPG, Runx2 and Bglap2 expression, and decreased RANKL expression in MC3T3-E1 cells. Silencing WISP2 rescued the effect of TRG-AS1 on BMMs and MC3T3-E1 cells. In vivo results showed that tumor volumes significantly decreased in mice injected with LV-TRG-AS1 transfected MDA-MB-231 cells. TRG-AS1 knockdown markedly reduced the number of TRAP+cells and the percentage of Ki-67+cells and decreased E-cadherin expression in xenograft tumor mice. In summary, TRG-AS1 acts an endogenous RNA, inhibited breast cancer bone metastasis by competitively binding with miR-877-5p to upregulate WISP2 expression.

Knockdown of MEF2D inhibits the development and progression of B-cell acute lymphoblastic leukemia.

Myocyte enhancer factor 2D (MEF2D) is involved in the progression of various malignant tumors. However, its impact on B-cell acute lymphoblastic leukemia (B-ALL) has not been elucidated. In this study, the expression level of MEF2D in B-ALL patients was validated through the Gene Expression Omnibus (GEO) database and clinical specimens. MEF2D-knockdown B-ALL cell lines were constructed by lentivirus transfection, and the effects of MEF2D on the viability, apoptosis, cycle progression, and drug sensitivity of B-ALL cells were verified by Cell Counting Kit-8 (CCK-8) and flow cytometry (FCM). The effect of MEF2D on the proliferation of B-ALL cells in vivo was verified via the construction of a xenograft mouse model. The mechanism of MEF2D regulating B-ALL cells was explored by RNA sequencing analysis, quantitative reverse transcription polymerase chain reaction (qRT-PCR), western blotting, and immunohistochemical (IHC). In this study, overexpression of MEF2D was observed in B-ALL patients and was remarkably correlated to disease progression in ALL patients. The knockdown of MEF2D expression suppressed cell viability, induced cell apoptosis, blockaded cell cycle progression, enhanced drug sensitivity of B-ALL cells in vitro, and reduced the tumor load in vivo. Furthermore, mechanistic studies revealed that MEF2D knockdown downregulated the expression of the phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K)-protein kinase B (AKT) signaling pathway. Our research demonstrated that MEF2D was markedly expressed in B-ALL. MEF2D knockdown inhibited cancer progression of B-ALL both in vitro and in vivo, which may be related to the downregulation of the PI3K-AKT signaling pathway. The data suggest that MEF2D plays a vital role in the process of tumorigenesis and may be a potential novel target for B-ALL therapy.

Reactive Oxygen Species-Triggered Hydrogen Sulfide Release and Cancer-Selective Antiproliferative Effect of Anethole Dithiolethione-Containing Polymeric Micelles.

Hydrogen sulfide (H2 S) is a gaseous signaling molecule in the human body and has attracted attention in cancer therapy due to its regulatory roles in cancer cell proliferation and migration. Accumulating evidence suggests that continuous delivery of H2 S to cancer cells for extended periods of time suppresses cancer progression. However, one major challenge in therapeutic applications of H2 S is its controlled delivery. To solve this problem, polymeric micelles are developed containing H2 S donating-anethole dithiolethione (ADT) groups, with H2 S release profiles optimal for suppressing cancer cell proliferation. The micelles release H2 S upon oxidation by reactive oxygens species (ROS) that are present inside the cells. The H2 S release profiles can be controlled by changing the polymer design. Furthermore, the micelles that show a moderate H2 S release rate exert the strongest anti-proliferative effect in human colon cancer cells in in vitro assays as well as the chick chorioallantoic membrane cancer model, while the micelles do not affect proliferation of human umbilical vein endothelial cells. This study shows the importance of fine-tuning H2 S release profiles using a micelle approach for realizing the full therapeutic potential of H2 S in cancer treatment.

Exosomal lncRNA NEAT1 induces paclitaxel resistance in breast cancer cells and promotes cell migration by targeting miR-133b

The lncRNA nuclear paraspeckle assembly transcript 1 (lncRNA NEAT1) has been associated with the development, metastasis and drug resistance of breast cancer (BC). However, the mechanisms underlying NEAT1-induced paclitaxel resistance in the microenvironment of BC remain unclear. In this study, NEAT1 expression was found to be high in paclitaxel-resistant BC cells (SKBR3/PR cells) and exosomes derived from these cells. NEAT1 promoted the migration of BC cells and their resistance to paclitaxel, whereas its downregulation reduced the drug resistance. In addition, downregulation of NEAT1 decreased the migration and proliferation of BC cells by inhibiting the expression of CXCL12 by reducing the adsorption of miR-133b. Furthermore, inhibition of miR-133b reversed the interference of NEAT1 and CXCL12 in paclitaxel resistance, migration and proliferation of BC cells. Knockdown of NEAT1 in a xenograft-bearing mouse model remarkably inhibited cancer progression and improved the response to paclitaxel. Altogether, this study revealed that SKBR3/PR cell-derived exosomal lncRNA NEAT1 can induce paclitaxel resistance and cell migration and growth in the tumour microenvironment of BC and may serve as a new target for the clinical treatment of BC.

Increased expression of GPX4 promotes the tumorigenesis of thyroid cancer by inhibiting ferroptosis and predicts poor clinical outcomes.

Ferroptosis plays a critical role in suppressing cancer progression, and its essential regulator is glutathione peroxidase 4 (GPX4). High GPX4 expression can inhibit accumulation of iron, thus suppressing ferroptosis. However, its function in thyroid cancer has not been fully illuminated. Here, we explore the effect of GPX4 on thyroid cancer tumorigenesis and prognosis. Based on The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases, GPX4 expression was investigated in cancer tissues and adjacent tissues. We determined the biological functions of GPX4-associated differentially expressed genes (DEGs) by using the "clusterProfiler" R package. In addition, the predictive value of GPX4 in thyroid cancer was assessed by using Cox regression analysis and nomograms. Finally, we conducted several in vitro experiments to determine the influence of GPX4 expression on proliferation and ferroptosis in thyroid cancer cells. GPX4 expression was obviously elevated in thyroid cancer tissues compared with normal tissues. Biological function analysis indicated enrichment in muscle contraction, contractile fiber, metal ion transmembrane transporter activity, and complement and coagulation cascades. GPX4 overexpression was associated with stage T3-T4 and pathologic stage III-IV in thyroid cancer patients. Cox regression analysis indicated that GPX4 may be a risk factor for the overall survival of thyroid cancer patients. In vitro research showed that knockdown of GPX4 suppressed proliferation and induced ferroptosis in thyroid cancer cells. GPX4 overexpression in thyroid cancer might play an essential role in tumorigenesis and may have prognostic value for thyroid cancer patients.

Drugs Targeting p53 Mutations with FDA Approval and in Clinical Trials.

Mutations in the tumor suppressor p53 (p53) promote cancer progression. This is mainly due to loss of function (LOS) as a tumor suppressor, dominant-negative (DN) activities of missense mutant p53 (mutp53) over wild-type p53 (wtp53), and wtp53-independent oncogenic activities of missense mutp53 by interacting with other tumor suppressors or oncogenes (gain of function: GOF). Since p53 mutations occur in ~50% of human cancers and rarely occur in normal tissues, p53 mutations are cancer-specific and ideal therapeutic targets. Approaches to target p53 mutations include (1) restoration or stabilization of wtp53 conformation from missense mutp53, (2) rescue of p53 nonsense mutations, (3) depletion or degradation of mutp53 proteins, and (4) induction of p53 synthetic lethality or targeting of vulnerabilities imposed by p53 mutations (enhanced YAP/TAZ activities) or deletions (hyperactivated retrotransposons). This review article focuses on clinically available FDA-approved drugs and drugs in clinical trials that target p53 mutations and summarizes their mechanisms of action and activities to suppress cancer progression.

PA2G4P4 Promotes Glioma Cell Migration and Tumorigenesis through the PTEN/AKT/mTOR Signaling Pathway

Dysregulation of pseudogene expression is closely related to the progression of various cancers, including glioma. Proliferation-associated 2G4 pseudogene 4 (PA2G4P4) could affect cell viability and apoptosis of glioma cells. However, the specific regulatory mechanism of PA2G4P4 is not clear. In this paper, we found that PA2G4P4 overexpres-sion promoted glioma cell proliferation, migration and cell cycle progression, whereas PA2G4P4 knockdown inhibited cancer progression. Knockdown of PA2G4P4 also suppressed the tumorigenesis of glioma cells in vivo. Furthermore, knockdown of PA2G4 after overexpression of PA2G4P4 decreased the cell viability and migration ability to normal level. The protein level of a tumor suppressor gene phosphatase and tensing homolog (PTEN) was greatly decreased in U87 cells after PA2G4P4 overexpression, while increased after PA2G4 knockdown; on the contrary, the protein levels of P-AKT and P-S6 were obviously induced in U87 cells after PA2G4P4 overexpression, and decreased after PA2G4 knockdown. The cell ability, colony formation ability and cell migration ability were all recovered to normal level by adding an AKT inhibitor MK2206 to the glioma cells, which were induced by PA2G4P4 overexpression. Our results revealed that PA2G4P4 could regulate glioma cell proliferation and migration through PTEN/AKT/mTOR signaling pathway by targeting PA2G4 gene. PA2G4P4 may become a target for glioma treatment.

A novel isoxazole compound CM2-II-173 inhibits the invasive phenotype of triple-negative breast cancer cells.

Invasion and metastasis are important hallmarks of breast cancer and are the leading cause of patient mortality. Triple-negative breast cancer (TNBC) is an aggressive type of breast cancer characterized by a poor prognosis and a lack of effective targeted therapies. The present study investigated the inhibitory effect of a novel FTY720 derivative on the invasive phenotype of TNBC cells. Here, we showed that a novel compound with an isoxazole ring, 4-(3-Decylisoxazol-5-yl)-1-hydroxy-2-(hydroxymethyl)butan-2-aminium chloride (CM2-II-173), significantly inhibited invasiveness of MDA-MB-231 TNBC cells. Expression of matrix metalloproteinase (MMP)-9 and invasiveness of MCF10A normal breast cells induced by sphingosine-1-phosphate (S1P) were reduced by CM2-II-173 treatment. Activations of pMEK1, pAkt, pERK, and p38 MAPK by S1P were inhibited by treatment with CM2-II-173. Proliferation and anchorage-independent growth of MDA-MB-231 TNBC cells were significantly decreased by CM2-II-173. CM2-II-173 efficiently induced apoptosis in MDA-MB-231 TNBC cells. CM2-II-173 significantly inhibited invasive phenotypes of breast, liver, prostate, and ovarian cancer cells. CM2-II-173 exhibited a more potent effect on the invasiveness of MDA-MB-231 TNBC cells compared to FTY720. Taken together, this study demonstrated that CM2-II-173 has the potential to be a lead compound that can inhibit cancer progression of not only TNBC cells, but also of liver, prostate, and ovarian cancer cells.

Quercetin acts as a novel anti-cancer drug to suppress cancer aggressiveness and cisplatin-resistance in nasopharyngeal carcinoma (NPC) through regulating the yes-associated protein/Hippo signaling pathway

BackgroundQuercetin has been proven to be effective for cancer treatment, including nasopharyngeal carcinoma (NPC). Also, Quercetin sensitizes cancer cells to current chemical drugs to improve their therapeutic efficacy. However, up until now, the molecular mechanisms that quercetin exerted its therapeutic effects on NPC have not been fully delineated. MethodsCell proliferation abilities were examined by CCK-8 assay and colony formation assay. Real-Time qPCR and Western Blot analysis were used to detect gene expressions at RNA and protein levels. Cell mobility was determined by wound scratch assay and transwell assay. Cell death was detected using flow cytometry (FCM). Tumorigenesis of the NPC cells was determined by in vivo tumor-bearing mice models. Hematoxylin and eosin (H&E) and TUNEL staining were used to detect the tumor metastasis to lung tissues and dead cells, respectively. ResultsHere, we validated that quercetin exerted its anti-tumor effects and increased cisplatin-sensitivity in NPC in vitro and in vivo. Specifically, quercetin inhibited NPC cell proliferation, viability, mobility, epithelial-mesenchymal transition (EMT), and tumorigenesis, and induced cell death, resulting in the inhibition of NPC progression. In addition, the NPC cells were subjected to a continuously increasing doses of cisplatin to generate cisplatin-resistant NPC (NPC/CDDP) cells. Interestingly, quercetin significantly enhanced the cytotoxic effects of high-dose cisplatin on NPC/CDDP cells. Furthermore, the potential underlying mechanisms were uncovered, and the results evidenced that quercetin inhibited Yes-associated protein (YAP) expression and its translocation to the nucleus, leading to the recovery of the Hippo pathway, inhibition of cancer progression, and increase in cisplatin-resistance. Mechanistically, upregulation of YAP by its gene manipulating vectors abrogated the inhibiting effects of quercetin on NPC malignant phenotypes, which also made NCP/CDDP cells irresponsive to high-dose cisplatin-quercetin co-treatments. ConclusionCollectively, our data evidenced that quercetin inhibited YAP to recover the Hippo pathway, which further inhibited NPC pathogenesis and increased susceptibility of NCP/CDDP cells to cisplatin treatment.

Correction: Tabrez et al. Targeting Glutaminase by Natural Compounds: Structure-Based Virtual Screening and Molecular Dynamics Simulation Approach to Suppress Cancer Progression. Molecules 2022, 27, 5042

Due to miscommunication, in the original publication there is a discrepancy in the project number and funding institution, located in Funding Information and Acknowledgement [...].

Anticarcinogenic impact of extracellular vesicles (exosomes) from cord blood stem cells in malignant melanoma: A potential biological treatment.

Incidence of Malignant Melanoma has become the 5th in the UK. To date, the major anticancer therapeutics include cell therapy, immunotherapy, gene therapy and nanotechnology-based strategies. Recently, extracellular vesicles, especially exosomes, have been highlighted for their therapeutic benefits in numerous chronic diseases. Exosomes display multifunctional properties, including inhibition of cancer cell proliferation and initiation of apoptosis. In the present in vitro study, the antitumour effect of cord blood stem cell (CBSC)-derived exosomes was confirmed by the CCK-8 assay (p < 0.05) on CHL-1 melanoma cells and improve the repair mechanism on lymphocytes from melanoma patients. Importantly, no significant effect was observed in healthy lymphocytes when treated with the exosome concentrations at 24, 48 and 72 h. Comet assay results (OTM and %Tail DNA) demonstrated that the optimal exosome concentration showed a significant impact (p < 0.05) in lymphocytes from melanoma patients whilst causing no significant DNA damage in lymphocytes of healthy volunteers was 300 μg/ml. Similarly, the Comet assay results depicted significant DNA damage in a melanoma cell line (CHL-1 cells) treated with CBSC-derived exosomes, both the cytotoxicity of CHL-1 cells treated with CBSC-derived exosomes exhibited a significant time-dependent decrease in cell survival. Sequencing analysis of CBSC exosomes showed the presence of the let-7 family of miRNAs, including let-7a-5p, let-7b-5p, let-7c-5p, let-7d-3p, let-7d-5p and two novel miRNAs. The potency of CBSC exosomes in inhibiting cancer progression in lymphocytes from melanoma patients and CHL-1 cells whilst causing no harm to the healthy lymphocytes makes it a potential candidate as an anticancer therapy.

Immunocyte Derived Exosomes: Insight into the Potential Chemo-immunotherapeutic Nanocarrier Targeting the Tumor Microenvironment.

"Cancer" is a dreadful immune-pathological condition that is characterized by anti-inflammatory and tumorigenic responses, elicited by the infiltrating immune cells in the vicinity of an uncontrollably proliferative tumor in the tumor microenvironment (TME). The TME offers a conducive microenvironment that supports cancer cell survival by modulating the host immune defense. Recent advancement in exosomal research has shown exosomes, originating from immune cells as well as the cancer cells, have immense potential for suppressing cancer progression and survival in the TME. Additionally, exosomes, irrespective of their diverse sources, have been reported to be efficient nanocarriers for cancer therapeutics with the ability for targeted delivery due to their biogenic nature, ease of cellular uptake, and scope for functionalization with biomolecules like peptides, aptamers, targeting ligands, etc. Immune cell-derived exosomes per se have been found efficacious against cancer owing to their immune-stimulant properties (in either naive or antigen primed form) even without loading any of cancer therapeutics or targeting ligand conjugation. Nevertheless, exosomes are being primarily explored as nanovesicular carriers for therapeutic molecules with different loading and targeting strategies, and the synergism between immunotherapeutic behavior of exosomes and the anticancer effect of the therapeutic molecules is yet to be explored. Hence, this review focuses specifically on the possible strategies to modulate the immunological nature of the source immune cells to obtain immune stimulant exosomes and bring these into the spotlight as chemo-immunotherapeutic nanovesicles, that can easily target and modulate the TME.

Hydrogen sulfide donors and inhibitors in cancer research: A state-of-the-art review

Hydrogen sulfide (H2S), a gaseous biomolecule, is considered a key player in the regulation of various essential cellular events. Normal physiology is determined by the level of endogenous H2S. Any alterations (upregulation and downregulation) to the level of endogenous H2S may lead to illness, including the onset of tumorigenesis. Over the past two decades, extensive research on the role of H2S in cancer development has affirmed the potential pharmacological means to suppress cancer progression by either inhibiting H2S synthesis in cells or exposing exogenously supplied H2S donors to treat different cancers. Some H2S donors and inhibitors release H2S or affect its synthesis. As a result, they have progressed through the development process into widespread clinical use and become increasingly important. The present study draws a detailed discussion on the types of H2S donors and inhibitors and their role in cancer research. We believe that this state-of-the-art review will empower the synthesis of H2S -based chemopreventive drugs and promote the need for further in-depth exploration of the associations between H2S and cancer treatments in clinical settings.

Metformin inhibits oral squamous cell carcinoma progression through regulating RNA alternative splicing

AimsOral squamous cell carcinoma (OSCC) is considered as the sixth most common cancer worldwide characterized by high invasiveness, high metastasis rate and high mortality. It is urgent to explore novel therapeutic strategies to overcome this feature. Metformin is currently a strong candidate anti-tumor drug in multiple cancers. However, whether metformin could inhibit cancer progression by regulating RNA alternative splicing remains largely unknown. Main methodsCell proliferation and growth ability of CAL-27 and UM-SCC6 were analyzed by CCK8 and colony formation assays. Cell migration was judged by wound healing assay. Mechanistically, RNA-seq was applied to systematically identify genes that are regulated by metformin. The expression of metformin-regulated genes was determined by real-time quantitative PCR (RT-qPCR). Metformin-regulated alternative splicing events were confirmed by RT-PCR. Key findingsWe demonstrated that metformin could significantly inhibit the proliferation and migration of oral squamous cell carcinoma cells. Mechanistically, in addition to transcriptional regulation, metformin induces a wide range of alternative splicing alteration, including genes involved in centrosome, cellular response to DNA damage stimulus, GTPase binding, histone modification, catalytic activity, regulation of cell cycle process and ATPase complex. Notably, metformin specifically modulates the splicing of NUBP2, a component of the cytosolic iron-sulfur (Fe/S) protein assembly (CIA). Briefly, metformin favors the production of NUBP2-L, the long splicing isoform of NUBP2, thereby inhibiting cancer cell proliferation. SignificanceOur findings provide mechanistic insights of metformin on RNA alternative splicing regulation, thus to offer a potential novel route for metformin to inhibit cancer progression.