Insights into the Pathogenesis and Treatment of Chemotherapy-Induced Neuropathy: A Focus on Oxidative Stress and Neuroinflammation.

Cancer is a high-morbidity disease prevalent worldwide. Chemotherapy is the primarily used regimen for cancer treatment; however, it also brings severe side effects. Chemotherapy-induced Peripheral Neuropathy (CIPN) and Chemotherapy-induced Cognitive Impairment (CICI) are two main complications occurring in chemotherapy. They are both associated with nervous system injury and are therefore collectively referred to as Chemotherapy-induced Neuropathy (CIN). CIPN induces neuralgia and numbness in limbs, while CICI causes amnesia and cognitive dysfunction. Currently, there are no effective therapeutics to prevent or cure CIN, so research into new drugs to alleviate CIN becomes urgent. Oxidative stress and neuroinflammation are the common pathogenic mechanisms of CIPN and CICI. Excessive Reactive Oxygen Species (ROS) and pro-inflammatory cytokines cause peripheral nervous system damage and hence CIPN. Peripheral ROS and cytokines also change the permeability of the blood-brain barrier, thereby increasing oxidative stress and neuroinflammation in the central nervous system, ultimately leading to CICI. Several antidepressants have been used to treat CIN and exhibited good clinical effects. Their potential pharmacological mechanism has been reported to ameliorate oxidative stress and neuroinflammation, guiding a new feasible way for effective therapeutic development against CIN. This mini-review has summarized the latest advances in the research on CIN with respect to clinical status, pathogenesis, and treatment. It has also discussed the potential of repurposing antidepressants for CIN treatment and prospected the strategy of developing therapeutics by targeting oxidative stress and neuroinflammation against CIN.

Antidepressant Sertraline Synergistically Enhances Paclitaxel Efficacy by Inducing Autophagy in Colorectal Cancer Cells.

Colorectal cancer (CRC) is the second leading cause of cancer-related death worldwide. It is important to discover new therapeutic regimens for treating CRC. Depression is known to be an important complication of cancer diseases. Repurposing antidepressants into anticancer drugs and exploring the combinational efficacy of antidepressants and chemotherapy are potentially good options for developing CRC treatment regimens. In this study, sertraline, an antidepressant drug, and paclitaxel, an anticancer drug, were chosen to study their antitumor effects in the treatment of colorectal cancer, alone or in combination, and to explore their underlying mechanisms. The data showed that sertraline exerted a dose-dependent cytotoxic effect on MC38 and CT26 colorectal cancer cell lines with IC50 values of 10.53 µM and 7.47 µM, respectively. Furthermore, sertraline synergistically sensitized chemotherapeutic agent paclitaxel efficacy in CRC cells with combination index (CI) values at various concentrations consistently lower than 1. Sertraline remarkably augmented paclitaxel-induced autophagy by increasing autophagosome formation indicated by elevated LC3-II/I ratio and promoting autophagic flux by degrading autophagy cargo receptor SQSTM1/p62, which may explain the synergistically cytotoxic effect of sertraline and paclitaxel combination therapy on CRC cells. This study provides important evidence to support repurposing sertraline as an anticancer agent and suggests a novel combinational regimen for effectively treating CRC as well as in the simultaneous treatment of CRC and depression.

αO-Conotoxin GeXIVA[1,2] Suppresses In Vivo Tumor Growth of Triple-Negative Breast Cancer by Inhibiting AKT-mTOR, STAT3 and NF-κB Signaling Mediated Proliferation and Inducing Apoptosis.

Breast cancer is one of the leading causes of cancer mortality worldwide, and triple-negative breast cancer (TNBC) is the most problematic subtype. There is an urgent need to develop novel drug candidates for TNBC. Marine toxins are a valuable source for drug discovery. We previously identified αO-conotoxin GeXIVA[1,2] from Conus generalis, which is a selective antagonist of α9 nicotinic acetylcholine receptors (nAChRs). Recent studies indicated that α9 nAChR expression is positively correlated with breast cancer development; thus, α9 nAChR could serve as a therapeutic target for breast cancer. In this study, we aimed to investigate the in vivo antitumor effects of GeXIVA[1,2] on TNBC and to elucidate its underlying anticancer mechanism. Our data showed that GeXIVA[1,2] effectively suppressed 4T1 tumor growth in vivo at a very low dose of 0.1 nmol per mouse. Our results uncovered that the antitumor mechanism of GeXIVA[1,2] simultaneously induced apoptosis and blocked proliferation. Further investigations revealed that GeXIVA[1,2]-induced Caspase-3-dependent apoptosis was achieved through regulating Bax/Bcl-2 balance, and GeXIVA[1,2]-inhibited proliferation was mediated by the downregulation of the AKT-mTOR, STAT3 and NF-κB signaling pathways. Our study provides valuable arguments to demonstrate the potential of GeXIVA[1,2] as a novel marine-derived anticancer drug candidate for the treatment of TNBC.

Diaporchalasin A, a new PDE4 inhibitory cytochalasin from Conus marmoreus-derived fungus Diaporthe sp. XMA007.

A novel cytochalasin named diaporchalasin A (1) bearing a cinnamenyl and an epoxy-macrocycloketone, and a new benzenepropionic acid derivative (2), and two known compounds (3 and 4) were isolated from Conus marmoreus-derived fungus Diaporthe sp. XMA007. Their structures were elucidated through detailed spectroscopic analysis, and the absolute configuration of 1 was determined by conformational analysis and TDDFT-ECD calculation. Their activity evaluation on PDE4 inhibition and breast cancer cell cytotoxicity were conducted, and compound 1 showed moderate inhibition on PDE4.

Emerging anticancer potential and mechanisms of snake venom toxins: A review.

Animal-derived venom, like snake venom, has been proven to be valuable natural resources for the drug development. Previously, snake venom was mainly investigated in its pharmacological activities in regulating coagulation, vasodilation, and cardiovascular function, and several marketed cardiovascular drugs were successfully developed from snake venom. In recent years, snake venom fractions have been demonstrated with anticancer properties of inducing apoptotic and autophagic cell death, restraining proliferation, suppressing angiogenesis, inhibiting cell adhesion and migration, improving immunity, and so on. A number of active anticancer enzymes and peptides have been identified from snake venom toxins, such as L-amino acid oxidases (LAAOs), phospholipase A2 (PLA2), metalloproteinases (MPs), three-finger toxins (3FTxs), serine proteinases (SPs), disintegrins, C-type lectin-like proteins (CTLPs), cell-penetrating peptides, cysteine-rich secretory proteins (CRISPs). In this review, we focus on summarizing these snake venom-derived anticancer components on their anticancer activities and underlying mechanisms. We will also discuss their potential to be developed as anticancer drugs in the future.

Antidepressants as Autophagy Modulators for Cancer Therapy.

Cancer is a major global public health problem with high morbidity. Depression is known to be a high-frequency complication of cancer diseases that decreases patients' life quality and increases the mortality rate. Therefore, antidepressants are often used as a complementary treatment during cancer therapy. During recent decades, various studies have shown that the combination of antidepressants and anticancer drugs increases treatment efficiency. In recent years, further emerging evidence has suggested that the modulation of autophagy serves as one of the primary anticancer mechanisms for antidepressants to suppress tumor growth. In this review, we introduce the anticancer potential of antidepressants, including tricyclic antidepressants (TCAs), tetracyclic antidepressants (TeCAs), selective serotonin reuptake inhibitors (SSRIs), and serotonin-norepinephrine reuptake inhibitors (SNRIs). In particular, we focus on their autophagy-modulating mechanisms for regulating autophagosome formation and lysosomal degradation. We also discuss the prospect of repurposing antidepressants as anticancer agents. It is promising to repurpose antidepressants for cancer therapy in the future.

Anti-Ovarian Cancer Conotoxins Identified from Conus Venom.

Conotoxins constitute a treasury of drug resources and have attracted widespread attention. In order to explore biological candidates from the marine cone snail, we isolated and identified three novel conopeptides named as Vi14b, Vi002, Vi003, three conotoxin variants named as Mr3d.1, Mr3e.1, Tx3a.1, and three known conotoxins (Vi15a, Mr3.8 and TCP) from crude venoms of Conus virgo, Conus marmoreus and Conus texile. Mr3.8 (I-V, II-VI, III-IV) and Tx3a.1 (I-III, II-VI, IV-V) both showed a novel pattern of disulfide connectivity, different from that previously established for the µ- and ψ-conotoxins. Concerning the effect on voltage-gated sodium channels, Mr3e.1, Mr3.8, Tx3a.1, TCP inhibited Nav1.4 or Nav1.8 by 21.51~24.32% of currents at semi-activated state (TP2) at 10 µmol/L. Certain anti-ovarian cancer effects on ID-8 cells were exhibited by Tx3a.1, Mr3e.1 and Vi14b with IC50 values of 24.29 µM, 54.97 µM and 111.6 µM, respectively. This work highlights the role of conotoxin libraries in subsequent drug discovery for ovarian cancer treatment.

Magnolol as a Potential Anticancer Agent: A Proposed Mechanistic Insight.

Cancer is a serious disease with high mortality and morbidity worldwide. Natural products have served as a major source for developing new anticancer drugs during recent decades. Magnolol, a representative natural phenolic lignan isolated from Magnolia officinali, has attracted considerable attention for its anticancer properties in recent years. Accumulating preclinical studies have demonstrated the tremendous therapeutic potential of magnolol via a wide range of pharmacological mechanisms against cancer. In this review, we summarized the latest advances in preclinical studies investigating anticancer properties of magnolol and described the important signaling pathways explaining its underlying mechanisms. Magnolol was capable of inhibiting cancer growth and metastasis against various cancer types. Magnolol exerted anticancer effects through inhibiting proliferation, inducing cell cycle arrest, provoking apoptosis, restraining migration and invasion, and suppressing angiogenesis. Multiple signaling pathways were also involved in the pharmacological actions of magnolol against cancer, such as PI3K/Akt/mTOR signaling, MAPK signaling and NF-κB signaling. Based on this existing evidence summarized in the review, we have conclusively confirmed magnolol had a multi-target anticancer effect against heterogeneous cancer disease. It is promising to develop magnolol as a drug candidate for cancer therapy in the future.

Conjugate of structurally reassigned pneumococcal serotype 31 polysaccharide with CRM197 elicited potent immune response.

Around 100 Streptococcus pneumonia (Spn) serotypes have been discovered, 90% of the severe diseases in children are caused by 13 serotypes. With the success of pneumococcal bacterial polysaccharide conjugate vaccines (PCVs), the burden of pneumococcal disease has been significantly reduced. Serotype 31 is a non-vaccine serotype and has increased in prevalence. By using Nuclear Magnetic Resonance (NMR) as the primary tool, we report the revised serotype 31 polysaccharide (s-31-ps) structure as [→3)-ß-D-Galf-(5/6-OAc)-(1 â†’ 3)-ß-D-Galp-(1 â†’ 3)-ß-L-Rhap-(2-OAc)-(1 â†’ 2)-α-L-Rhap-(1 â†’ 4)-ß-D-GlcpA-(1→]n. Furthermore, the reductive amination-conjugate of serotype 31 polysaccharide and cross reacting material (CRM197) protein was prepared in organic solvent (N,N-dimethylformamide, DMF) instead of water. The reaction is faster, and the DMF conjugate elicited comparable immune responses with the aqueous conjugate. S-31-ps conjugate vaccine has the potential of being included in the next-generation PCV vaccines.

Patient-Derived Organoids Can Guide Personalized-Therapies for Patients with Advanced Breast Cancer.

Most breast cancers at an advanced stage exhibit an aggressive nature, and there is a lack of effective anticancer options. Herein, the development of patient-derived organoids (PDOs) is described as a real-time platform to explore the feasibility of tailored treatment for refractory breast cancers. PDOs are successfully generated from breast cancer tissues, including heavily treated specimens. The microtubule-targeting drug-sensitive response signatures of PDOs predict improved distant relapse-free survival for invasive breast cancers treated with adjuvant chemotherapy. It is further demonstrated that PDO pharmaco-phenotyping reflects the previous treatment responses of the corresponding patients. Finally, as clinical case studies, all patients who receive at least one drug predicate to be sensitive by PDOs achieve good responses. Altogether, the PDO model is developed as an effective platform for evaluating patient-specific drug sensitivity in vitro, which can guide personal treatment decisions for breast cancer patients at terminal stage.

Molecular landscape and subtype-specific therapeutic response of nasopharyngeal carcinoma revealed by integrative pharmacogenomics.

Nasopharyngeal carcinoma (NPC) is a malignant head and neck cancer type with high morbidity in Southeast Asia, however the pathogenic mechanism of this disease is poorly understood. Using integrative pharmacogenomics, we find that NPC subtypes maintain distinct molecular features, drug responsiveness, and graded radiation sensitivity. The epithelial carcinoma (EC) subtype is characterized by activations of microtubule polymerization and defective mitotic spindle checkpoint related genes, whereas sarcomatoid carcinoma (SC) and mixed sarcomatoid-epithelial carcinoma (MSEC) subtypes exhibit enriched epithelial-mesenchymal transition (EMT) and invasion promoting genes, which are well correlated with their morphological features. Furthermore, patient-derived organoid (PDO)-based drug test identifies potential subtype-specific treatment regimens, in that SC and MSEC subtypes are sensitive to microtubule inhibitors, whereas EC subtype is more responsive to EGFR inhibitors, which is synergistically enhanced by combining with radiotherapy. Through combinational chemoradiotherapy (CRT) screening, effective CRT regimens are also suggested for patients showing less sensitivity to radiation. Altogether, our study provides an example of applying integrative pharmacogenomics to establish a personalized precision oncology for NPC subtype-guided therapies.

Upregulation of amplified in breast cancer 1 contributes to pancreatic ductal adenocarcinoma progression and vulnerability to blockage of hedgehog activation.

Background: Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive and devastating cancers without effective treatments. Amplified in breast cancer 1 (AIB1) is a member of the steroid receptor coactivator family that mediates the transcriptional activities of nuclear receptors. While AIB1 is associated with the initiation and progression of multiple cancers, the mechanism by which AIB1 contributes to PDAC progression remains unknown. In this study, we aimed to explore the role of AIB1 in the progression of PDAC and elucidate the underlying mechanisms. Methods: The clinical significance and mRNA level of AIB1 in PDAC were studied by database analysis. To demonstrate whether AIB1 mediates the malignant features of PDAC cells, namely, proliferation, migration, invasion, we performed real-time PCR and Western blot analysis, established xenograft models and used in vivo metastasis assay. With insights into the mechanism of AIB1, we performed RNA sequencing (Seq), ChIP-Seq, luciferase reporter assays and pull-down assays. Furthermore, we analyzed the relationship between AIB1 expression and its target expression in PDAC cells and patients and explored whether PDAC cells with high AIB1 levels are sensitive to inhibitors of its target. Results: We found that AIB1 was significantly upregulated in PDAC and associated with its malignancy. Silencing AIB1 impaired hedgehog (Hh) activation by reducing the expression of smoothened (SMO), leading to cell cycle arrest and the inhibition of PDAC cell proliferation. In addition, AIB1, via upregulation of integrin αv (ITGAV) expression, promoted extracellular matrix (ECM) signaling, which played an important role in PDAC progression. Further studies showed that AIB1 preferably bound to AP-1 related elements and served as a coactivator for enhancing the transcriptional activity of MafB, which promoted the expression of SMO and ITGAV. PDAC cells with high AIB1 levels were sensitive to Hh signaling inhibitors, suggesting that blocking Hh activation is an effective treatment against PDAC with high AIB1 expression. Conclusions: These findings reveal that AIB1 is a crucial oncogenic regulator associated with PDAC progression via Hh and ECM signaling and suggest potential therapeutic targets for PDAC treatment.

NOTCH1 activation compensates BRCA1 deficiency and promotes triple-negative breast cancer formation.

BRCA1 mutation carriers have a higher risk of developing triple-negative breast cancer (TNBC), which is a refractory disease due to its non-responsiveness to current clinical targeted therapies. Using the Sleeping Beauty transposon system in Brca1-deficient mice, we identified 169 putative cancer drivers, among which Notch1 is a top candidate for accelerating TNBC by promoting the epithelial-mesenchymal transition (EMT) and regulating the cell cycle. Activation of NOTCH1 suppresses mitotic catastrophe caused by BRCA1 deficiency by restoring S/G2 and G2/M cell cycle checkpoints, which may through activation of ATR-CHK1 signalling pathway. Consistently, analysis of human breast cancer tissue demonstrates NOTCH1 is highly expressed in TNBCs, and the activated form of NOTCH1 correlates positively with increased phosphorylation of ATR. Additionally, we demonstrate that inhibition of the NOTCH1-ATR-CHK1 cascade together with cisplatin synergistically kills TNBC by targeting the cell cycle checkpoint, DNA damage and EMT, providing a potent clinical option for this fatal disease.

αO-Conotoxin GeXIVA Inhibits the Growth of Breast Cancer Cells via Interaction with α9 Nicotine Acetylcholine Receptors.

The α9-containing nicotinic acetylcholine receptor (nAChR) is increasingly emerging as a new tumor target owing to its high expression specificity in breast cancer. αO-Conotoxin GeXIVA is a potent antagonist of α9α10 nAChR. Nevertheless, the anti-tumor effect of GeXIVA on breast cancer cells remains unclear. Cell Counting Kit-8 assay was used to study the cell viability of breast cancer MDA-MD-157 cells and human normal breast epithelial cells, which were exposed to different doses of GeXIVA. Flow cytometry was adopted to detect the cell cycle arrest and apoptosis of GeXIVA in breast cancer cells. Migration ability was analyzed by wound healing assay. Western blot (WB), quantitative real-time PCR (QRT-PCR) and flow cytometry were used to determine expression of α9-nAChR. Stable MDA-MB-157 breast cancer cell line, with the α9-nAChR subunit knocked out (KO), was established using the CRISPR/Cas9 technique. GeXIVA was able to significantly inhibit the proliferation and promote apoptosis of breast cancer MDA-MB-157 cells. Furthermore, the proliferation of breast cancer MDA-MB-157 cells was inhibited by GeXIVA, which caused cell cycle arrest through downregulating α9-nAChR. GeXIVA could suppress MDA-MB-157 cell migration as well. This demonstrates that GeXIVA induced a downregulation of α9-nAChR expression, and the growth of MDA-MB-157 α9-nAChR KO cell line was inhibited as well, due to α9-nAChR deletion. GeXIVA inhibits the growth of breast cancer cell MDA-MB-157 cells in vitro and may occur in a mechanism abolishing α9-nAChR.

BRCA1 Deficiency Impairs Mitophagy and Promotes Inflammasome Activation and Mammary Tumor Metastasis.

The breast cancer susceptibility gene 1 (BRCA1) is a major tumor suppressor gene and is most frequently mutated in hereditary breast cancer. BRCA1 plays a critical role in many biological processes, especially maintaining genomic stability in the nucleus, yet its role in the cytoplasm remains elusive. Here, it is revealed that BRCA1 maintains a healthy mitochondrial network through regulating mitochondrial dynamics, including fission and fusion. BRCA1 deficiency causes dysfunctional mitochondrial dynamics through increased expression of mitofusin1/2. With mitochondrial stress, BRCA1 is recruited to the mitochondrial outer membrane, where it plays an essential role in maintaining a healthy mitochondrial network. Consequently, BRCA1 deficiency impairs stress-induced mitophagy through blocking ataxia-telangiectasia mutated (ATM)-AMP-activated protein kinase (AMPK)-Dynamin-related protein 1 (DRP1)-mediated mitochondrial fission and triggers NLRP3 inflammasome activation, which creates a tumor-associated microenvironment, thereby facilitating tumor proliferation and metastasis. It is further shown that inflammasome inhibition can prevent tumor recurrence and metastasis. This study uncovers an important role of BRCA1 in regulating mitophagy and suggests a therapeutic approach for fighting this deadly disease.

Flavonoids from Rhynchosia minima root exerts anti-inflammatory activity in lipopolysaccharide-stimulated RAW 264.7 cells via MAPK/NF-κB signaling pathway.

Rhynchosia minima root, a folk herbal medicine in southern China, is used to relieve itch and swelling. In this study, we examined the anti-inflammatory property of an ethanol fraction (EEF6) from R. minima root on lipopolysaccharide (LPS)-induced RAW 264.7 cells, as well as its underlying mechanism. The compound composition of EEF6 was determined by high-performance liquid chromatography-mass spectrometry. The result showed that five flavonoids compounds, 2',4',5,7-tetrahydroxyisoflavone, genistein-8-C-glucopyranoside, tricin, genistein, and daidzein, were identified in EEF6. In addition, EEF6 exhibited potent anti-inflammatory ability against LPS-stimulated RAW 264.7 cells via MAPK/NF-κB signaling pathways by decreasing the secretion of nitric oxide (NO), interleukin (IL)-6, TNF-α, and monocyte chemotactic protein (MCP)-1, inhibiting the translocation of p65 from cytoplasm to nucleus, and suppressing the phosphorylation of ERK, JNK, and p38. These results indicated that EEF6 could be a promising ingredient for inflammation management.

Fast identification of anticancer constituents in Forsythiae Fructus based on metabolomics approaches.

An herb commonly contains hundreds of constituents. Identification of bioactive compound(s) in each herb using conventional approaches is usually inefficient and eco-unfriendly. In this study, we aimed to fast identify anticancer compounds in Forsythiae Fructus using UPLC/MS-based metabolomics analysis. We firstly fractionated Forsythiae Fructus crude extracts with organic solvents of different polarity, then the chemical profile of each fraction was analyzed by UPLC/Q-TOF/MS, and the anticancer activity profiles of all fractions were determined by MTT assay. Next, orthogonal projections to latent structures discriminant analysis (OPLS-DA) was applied to discriminate fractions with different anticancer activity to determine the compound(s) that contributes most to the anticancer activity. Betulinic acid was then identified to be the most potent anticancer compound in Forsythiae Fructus. Its predicted anticancer activity was confirmed by MTT assay. Taken together, our results demonstrated that the present integrated metabolomics strategy could be used for fast identification of anticancer compound(s) in herb extracts or other complex mixtures of chemicals.

Differences in Chemical Component and Anticancer Activity of Green and Ripe Forsythiae Fructus.

Forsythiae Fructus, Lianqiao in Chinese, is one of the most fundamental herbs in Traditional Chinese Medicine. Both green Forsythia (GF) and ripe Forsythia (RF) are referred to Forsythiae Fructus in medicinal applications. In most cases, they are used without distinction. In this study, a metabolomics approach was performed to compare componential differences of two Forsythiae Fructus aqueous extracts subtypes. Principal component analysis (PCA) score plots from the UPLC-MS data showed clear separation between the two subtypes, indicating there are significant differences in the chemical components between GF and RF. Meanwhile, the anticancer activity of them was also compared. GF exhibited much stronger antitumor activity than RF against B16-F10 murine melanoma both in vitro and in vivo. 15 chemical compounds were identified as specific markers for distinguishing GF and RF. Among these marker compounds, forsythoside I, forsythoside A, forsythoside E and pinoresinol were demonstrated to be key important active compounds that account for the different anticancer efficacies of GF and RF. Our data suggest that GF and RF should be distinctively used in clinical applications, particularly in the anticancer formulas, in which GF should be preferentially prescribed.

Emerging roles of SIRT1 in fatty liver diseases.

Fatty liver diseases, which are commonly associated with high-fat/calorie diet, heavy alcohol consumption and/or other metabolic disorder causes, lead to serious medical concerns worldwide in recent years. It has been demonstrated that metabolic homeostasis disruption is most likely to be responsible for this global epidemic. Sirtuins are a group of conserved nicotinamide adenine dinucleotide (NAD+) dependent histone and/or protein deacetylases belonging to the silent information regulator 2 (Sir2) family. Among seven mammalian sirtuins, sirtuin 1 (SIRT 1) is the most extensively studied one and is involved in both alcoholic and nonalcoholic fatty liver diseases. SIRT1 plays beneficial roles in regulating hepatic lipid metabolism, controlling hepatic oxidative stress and mediating hepatic inflammation through deacetylating some transcriptional regulators against the progression of fatty liver diseases. Here we summarize the latest advances of the biological roles of SIRT1 in regulating lipid metabolism, oxidative stress and inflammation in the liver, and discuss the potential of SIRT1 as a therapeutic target for treating alcoholic and nonalcoholic fatty liver diseases.