Exosome-mediated miR-200a delivery into TGF-ß-treated AGS cells abolished epithelial-mesenchymal transition with normalization of ZEB1, vimentin and Snail1 expression.

Exosomes are small extracellular vesicles that can be derived from human cells such as mesenchymal stem cells (MSCs). The size of exosomes is at nano-scale range and owing to their biocompatibility and other characteristics, they have been promising candidates for delivery of bioactive compounds and genetic materials in disease therapy, especially cancer therapy. Gastric cancer (GC) is a leading cause of death among patients and this malignant disease affects gastrointestinal tract that its invasiveness and abnormal migration mediate poor prognosis of patients. Metastasis is an increasing challenge in GC and microRNAs (miRNAs) are potential regulators of metastasis and related molecular pathways, especially epithelial-to-mesenchymal transition (EMT). In the present study, our aim was to explore role of exosomes in miR-200a delivery for suppressing EMT-mediated GC metastasis. Exosomes were isolated from MSCs via size exclusion chromatography. The synthetic miR-200a mimics were transfected into exosomes via electroporation. AGS cell line exposed to TGF-ß for EMT induction and then, these cells cultured with miR-200a-loaded exosomes. The transwell assays performed to evaluate GC migration and expression levels of ZEB1, Snail1 and vimentin measured. Exosomes demonstrated loading efficiency of 5.92 ± 4.6%. The TGF-ß treatment transformed AGS cells into fibroblast-like cells expressing two stemness markers, CD44 (45.28%) and CD133 (50.79%) and stimulated EMT. Exosomes induced a 14.89-fold increase in miR-200a expression in AGS cells. Mechanistically, miR-200a enhances E-cadherin levels (P < 0.01), while it decreases expression levels of ß-catenin (P < 0.05), vimentin (P < 0.01), ZEB1 (P < 0.0001) and Snail1 (P < 0.01), leading to EMT inhibition in GC cells. This pre-clinical experiment introduces a new strategy for miR-200a delivery that is of importance for preventing migration and invasion of GC cells.

MicroRNAs regulating SOX2 in cancer progression and therapy response.

The proliferation, metastasis and therapy response of tumour cells are tightly regulated by interaction among various signalling networks. The microRNAs (miRNAs) can bind to 3'-UTR of mRNA and down-regulate expression of target gene. The miRNAs target various molecular pathways in regulating biological events such as apoptosis, differentiation, angiogenesis and migration. The aberrant expression of miRNAs occurs in cancers and they have both tumour-suppressor and tumour-promoting functions. On the contrary, SOX proteins are capable of binding to DNA and regulating gene expression. SOX2 is a well-known member of SOX family that its overexpression in different cancers to ensure progression and stemness. The present review focuses on modulatory impact of miRNAs on SOX2 in affecting growth, migration and therapy response of cancers. The lncRNAs and circRNAs can function as upstream mediators of miRNA/SOX2 axis in cancers. In addition, NF-κB, TNF-α and SOX17 are among other molecular pathways regulating miRNA/SOX2 axis in cancer. Noteworthy, anti-cancer compounds including bufalin and ovatodiolide are suggested to regulate miRNA/SOX2 axis in cancers. The translation of current findings to clinical course can pave the way to effective treatment of cancer patients and improve their prognosis.

Caffeic acid and its derivatives as potential modulators of oncogenic molecular pathways: New hope in the fight against cancer.

As a phenolic acid compound, caffeic acid (CA) can be isolated from different sources such as tea, wine and coffee. Caffeic acid phenethyl ester (CAPE) is naturally occurring derivative of CA isolated from propolis. This medicinal plant is well-known due to its significant therapeutic impact including its effectiveness as hepatoprotective, neuroprotective and anti-diabetic agent. Among them, anti-tumor activity of CA has attracted much attention, and this potential has been confirmed both in vitro and in vivo. CA can induce apoptosis in cancer cells via enhancing ROS levels and impairing mitochondrial function. Molecular pathways such as PI3K/Akt and AMPK with role in cancer progression, are affected by CA and its derivatives in cancer therapy. CA is advantageous in reducing aggressive behavior of tumors via suppressing metastasis by inhibiting epithelial-to-mesenchymal transition mechanism. Noteworthy, CA and CAPE can promote response of cancer cells to chemotherapy, and sensitize them to chemotherapy-mediated cell death. In order to improve capacity of CA and CAPE in cancer suppression, it has been co-administered with other anti-tumor compounds such as gallic acid and p-coumaric acid. Due to its poor bioavailability, nanocarriers have been developed for enhancing its ability in cancer suppression. These issues have been discussed in the present review with a focus on molecular pathways to pave the way for rapid translation of CA for clinical use.

Nrf2 signaling pathway in cisplatin chemotherapy: Potential involvement in organ protection and chemoresistance.

Nuclear factor erythroid 2-related factor 2 (Nrf2) is a vital transcription factor and its induction is of significant importance for protecting against oxidative damage. Increased levels of Reactive Oxygen Species (ROS) stimulate Nrf2 signaling, enhancing the activity of antioxidant enzymes such as catalase, superoxide dismutase and glutathione peroxidase. These enzymes are associated with retarding oxidative stress. On the other hand, Nrf2 activation in cancer cells is responsible for the development of chemoresistance due to disrupting oxidative mediated-cell death by reducing ROS levels. Cisplatin (CP), cis-diamminedichloroplatinum(II), is a potent anti-tumor agent extensively used in cancer therapy, but its frequent application leads to the development of chemoresistance as well. In the present study, association of Nrf2 signaling with chemoresistance to CP and protection against its deleterious effects is discussed. Anti-tumor compounds, mainly phytochemicals, retard chemoresistance by suppressing Nrf2 signaling. Upstream mediators such as microRNAs can regulate Nrf2 expression during CP chemotherapy regimens. Protection against side effects of CP is mediated via activating Nrf2 signaling and its downstream targets activating antioxidant defense system. Protective agents that activate Nrf2 signaling, can ameliorate CP-mediated ototoxicity, nephrotoxicity and neurotoxicity. Reducing ROS levels and preventing cell death are the most important factors involved in alleviating CP toxicity upon Nrf2 activation. As pre-clinical experiments advocate the role of Nrf2 in chemoprotection and CP resistance, translating these findings to the clinic can provide a significant progress in treatment of cancer patients.

Novel combination therapy for respiratory diseases of small ruminants: Field studies of over 10 years.

Objective: This study aimed to evaluate a new drug combination for small ruminant respiratory diseases to find a better treatment protocol for the potential replacement of older methods. Materials and Methods: A total of 6,886 animals received common respiratory disease therapies out of 15,845 animals that had respiratory disorders. The new combination therapy technique treated the remaining animals (8,968). The animals were given an oral suspension of triclabendazole or levamisole at an initial dosage of 0.2 ml/kg body weight (BW). The following day, 0.2 mg/kg of 1% ivermectin was subcutaneously administered. Then, on the third and fifth days of treatment, a subcutaneous injection of 30 mg/kg BW of florfenicol (30%) was administered. The survival and recovery rates for both groups were tracked throughout a 6-month period of observation. Postmortem and histopathological signs were also assessed. Results: In the group of the novel combination therapy, group A, clinical, postmortem, and histopathological signs were significantly reduced compared to group B. Clinical signs and mortality in group A were 90% and 93% lower than in group B, respectively. Animals that received the new combination therapy were healed of their disease and stayed immune for 6 months. Conclusion: This novel therapy demonstrated significant efficacy against respiratory diseases in a 10-year field study. The paper proved that the protocol introduced could be a new therapeutic approach.

The potential immunomodulatory effect of levamisole in humans and farm animals.

This study conducted a literature review to investigate the immunomodulatory effect of levamisole in both humans and farm animals. The following procedure was followed for database searching: PubMed, Google Scholar, Web of Science, and Cochrane Library. All research works were updated to September 2022. The terms used in the literature search were included: ("levamisole" OR "immunity" OR "immune system") AND ("adjuvant" OR "fish" OR "poultry" OR "farm animal" OR "cattle" OR "sheep"). The current review enlightens the extensive potential of levamisole as an adjuvant immunotherapeutic agent and explains its divergent applications beyond its antiparasitic use as an adjuvant, dietary supplement, immunostimulant, antiviral, and anti-cancer drug in humans and farm animals. In the articles examined, various mechanisms have been proposed for levamisole immunoprotective effects, but hormonal alteration and stress hormone reduction are indicated as the main mechanisms in various animal species.

Resveratrol Augments Doxorubicin and Cisplatin Chemotherapy: A Novel Therapeutic Strategy.

BACKGROUND: The treatment of cancer is a current challenge for public health, causing high rates of morbidity and mortality worldwide. Doxorubicin (DOX) and cisplatin (CP) are two well-known chemotherapeutic agents approved by the Food and Drug Administration to treat cancer patients. However, there are two problems associated with DOX and CP: drug resistance and adverse impact. Resveratrol (Res) belongs to the stilbene class and possesses various health-promoting effects, such as antioxidant, anti-inflammatory, anticancer, hepatoprotective, and neuroprotective effects. OBJECTIVE: The present review aims to give special attention to the therapeutic impacts of Res in potentiating DOX and CP's antitumor activities and reducing their side effects. METHODS: PubMed, Science Direct, and Google Scholar were used to search articles for the current manuscripts. RESULTS: Co-administration of Res can prevent chemoresistance and potentiate the induction of apoptosis and cell cycle arrest in cancer cells. Res can enhance the sensitivity of cancer cells to DOX and CP chemotherapy by inhibiting the migration and metastasis of cancer cells. Simultaneously, Res, due to its therapeutic actions ameliorates the adverse impacts of DOX and CP on normal cells and organs, including the liver, kidney, brain, and testes. As Res suffers from poor bioavailability, nanoformulations have been developed with promising results to improve its antitumor activity and protective effects. CONCLUSION: Based on preclinical studies, it is obvious that Res is a promising adjsuvant for CP and DOX chemotherapy, and its benefits can be utilized in the clinical course.

Advances in understanding the role of P-gp in doxorubicin resistance: Molecular pathways, therapeutic strategies, and prospects.

P-glycoprotein (P-gp) is a drug efflux transporter that triggers doxorubicin (DOX) resistance. In this review, we highlight the molecular avenues regulating P-gp, such as Nrf2, HIF-1α, miRNAs, and long noncoding (lnc)RNAs, to reveal their participation in DOX resistance. These antitumor compounds and genetic tools synergistically reduce P-gp expression. Furthermore, ATP depletion impairs P-gp activity to enhance the antitumor activity of DOX. Nanoarchitectures, including liposomes, micelles, polymeric nanoparticles (NPs), and solid lipid nanocarriers, have been developed for the co-delivery of DOX with anticancer compounds and genes enhancing DOX cytotoxicity. Surface modification of nanocarriers, for instance with hyaluronic acid (HA), can promote selectivity toward cancer cells. We discuss these aspects with a focus on P-gp expression and activity.

Molecular Landscape of LncRNAs in Prostate Cancer: A focus on pathways and therapeutic targets for intervention.

BACKGROUND: One of the most malignant tumors in men is prostate cancer that is still incurable due to its heterogenous and progressive natures. Genetic and epigenetic changes play significant roles in its development. The RNA molecules with more than 200 nucleotides in length are known as lncRNAs and these epigenetic factors do not encode protein. They regulate gene expression at transcriptional, post-transcriptional and epigenetic levels. LncRNAs play vital biological functions in cells and in pathological events, hence their expression undergoes dysregulation. AIM OF REVIEW: The role of epigenetic alterations in prostate cancer development are emphasized here. Therefore, lncRNAs were chosen for this purpose and their expression level and interaction with other signaling networks in prostate cancer progression were examined. KEY SCIENTIFIC CONCEPTS OF REVIEW: The aberrant expression of lncRNAs in prostate cancer has been well-documented and progression rate of tumor cells are regulated via affecting STAT3, NF-κB, Wnt, PI3K/Akt and PTEN, among other molecular pathways. Furthermore, lncRNAs regulate radio-resistance and chemo-resistance features of prostate tumor cells. Overexpression of tumor-promoting lncRNAs such as HOXD-AS1 and CCAT1 can result in drug resistance. Besides, lncRNAs can induce immune evasion of prostate cancer via upregulating PD-1. Pharmacological compounds such as quercetin and curcumin have been applied for targeting lncRNAs. Furthermore, siRNA tool can reduce expression of lncRNAs thereby suppressing prostate cancer progression. Prognosis and diagnosis of prostate tumor at clinical course can be evaluated by lncRNAs. The expression level of exosomal lncRNAs such as lncRNA-p21 can be investigated in serum of prostate cancer patients as a reliable biomarker.

The long and short non-coding RNAs modulating EZH2 signaling in cancer.

Non-coding RNAs (ncRNAs) are a large family of RNA molecules with no capability in encoding proteins. However, they participate in developmental and biological processes and their abnormal expression affects cancer progression. These RNA molecules can function as upstream mediators of different signaling pathways and enhancer of zeste homolog 2 (EZH2) is among them. Briefly, EZH2 belongs to PRCs family and can exert functional roles in cells due to its methyltransferase activity. EZH2 affects gene expression via inducing H3K27me3. In the present review, our aim is to provide a mechanistic discussion of ncRNAs role in regulating EZH2 expression in different cancers. MiRNAs can dually induce/inhibit EZH2 in cancer cells to affect downstream targets such as Wnt, STAT3 and EMT. Furthermore, miRNAs can regulate therapy response of cancer cells via affecting EZH2 signaling. It is noteworthy that EZH2 can reduce miRNA expression by binding to promoter and exerting its methyltransferase activity. Small-interfering RNA (siRNA) and short-hairpin RNA (shRNA) are synthetic, short ncRNAs capable of reducing EZH2 expression and suppressing cancer progression. LncRNAs mainly regulate EZH2 expression via targeting miRNAs. Furthermore, lncRNAs induce EZH2 by modulating miRNA expression. Circular RNAs (CircRNAs), like lncRNAs, affect EZH2 expression via targeting miRNAs. These areas are discussed in the present review with a focus on molecular pathways leading to clinical translation.

Targeting autophagy in prostate cancer: preclinical and clinical evidence for therapeutic response.

Prostate cancer is a leading cause of death worldwide and new estimates revealed prostate cancer as the leading cause of death in men in 2021. Therefore, new strategies are pertinent in the treatment of this malignant disease. Macroautophagy/autophagy is a "self-degradation" mechanism capable of facilitating the turnover of long-lived and toxic macromolecules and organelles. Recently, attention has been drawn towards the role of autophagy in cancer and how its modulation provides effective cancer therapy. In the present review, we provide a mechanistic discussion of autophagy in prostate cancer. Autophagy can promote/inhibit proliferation and survival of prostate cancer cells. Besides, metastasis of prostate cancer cells is affected (via induction and inhibition) by autophagy. Autophagy can affect the response of prostate cancer cells to therapy such as chemotherapy and radiotherapy, given the close association between autophagy and apoptosis. Increasing evidence has demonstrated that upstream mediators such as AMPK, non-coding RNAs, KLF5, MTOR and others regulate autophagy in prostate cancer. Anti-tumor compounds, for instance phytochemicals, dually inhibit or induce autophagy in prostate cancer therapy. For improving prostate cancer therapy, nanotherapeutics such as chitosan nanoparticles have been developed. With respect to the context-dependent role of autophagy in prostate cancer, genetic tools such as siRNA and CRISPR-Cas9 can be utilized for targeting autophagic genes. Finally, these findings can be translated into preclinical and clinical studies to improve survival and prognosis of prostate cancer patients.

Molecular landscape of c-Myc signaling in prostate cancer: A roadmap to clinical translation.

The c-Myc signaling is a new emerging target in cancer therapy. Activation of c-Myc signaling leads to cancer growth and invasion in vitro and in vivo. The stability of c-Myc can also mediate drug resistance and radioresistance in cancers. The apoptosis inhibition and enhancing cell cycle progression are mediated by c-Myc overexpression. On the other hand, prostate cancer (PC) is the most common cancer in men and causes high death. The present review focuses on c-Myc signaling in PC. The c-Myc overexpression is in favor of PC growth and migration. Upon c-Myc inhibition, apoptosis and cell cycle arrest (G0/G1 phase) occur in PC cells. The c-Myc induces glycolysis in enhancing PC growth. Besides, stability and overexpression of c-Myc can mediate resistance of PC cells to chemotherapy and radiotherapy. The inhibition of c-Myc by both anti-tumor agents and genetic tools suppress PC progression. The miRNAs, lncRNAs, circRNAs and other factors such as PI3K/Akt can act as upstream regulator of c-Myc signaling. The c-Myc can function as independent prognostic and diagnostic factor in PC patients. The c-Myc upregulation is associated with reduced overall survival, clinical stage, lymph node metastasis and undesirable prognosis of PC patients.

EZH2 as a new therapeutic target in brain tumors: Molecular landscape, therapeutic targeting and future prospects.

Brain tumors are responsible for high mortality and morbidity worldwide. The brain tumor treatment depends on identification of molecular pathways involved in progression and malignancy. Enhancer of zeste homolog 2 (EZH2) has obtained much attention in recent years in field of cancer therapy due to its aberrant expression and capacity in modulating expression of genes by binding to their promoter and affecting methylation status. The present review focuses on EZH2 signaling in brain tumors including glioma, glioblastoma, astrocytoma, ependymomas, medulloblastoma and brain rhabdoid tumors. EZH2 signaling mainly participates in increasing proliferation and invasion of cancer cells. However, in medulloblastoma, EZH2 demonstrates tumor-suppressor activity. Furthermore, EZH2 can regulate response of brain tumors to chemotherapy and radiotherapy. Various molecular pathways can function as upstream mediators of EZH2 in brain tumors including lncRNAs and miRNAs. Owing to its enzymatic activity, EZH2 can bind to promoter of target genes to induce methylation and affects their expression. EZH2 can be considered as an independent prognostic factor in brain tumors that its upregulation provides undesirable prognosis. Both anti-tumor agents and gene therapies such as siRNA have been developed for targeting EZH2 in cancer therapy.

Doxorubicin-loaded graphene oxide nanocomposites in cancer medicine: stimuli-responsive carriers, co-delivery and suppressing resistance.

INTRODUCTION: The application of doxorubicin (DOX) in cancer therapy has been limited due to its drug resistance and poor internalization. Graphene oxide (GO) nanostructures have the capacity for DOX delivery while promoting its cytotoxicity in cancer. AREAS COVERED: The favorable characteristics of GO nanocomposites, preparation method, and application in cancer therapy are described. Then, DOX resistance in cancer, GO-mediated photothermal therapy, and DOX delivery for cancer suppression are described. Preparation of stimuli-responsive GO nanocomposites, surface functionalization, hybrid nanoparticles, and theranostic applications are emphasized in DOX chemotherapy. EXPERT OPINION: GO nanoparticle-based photothermal therapy maximizes the anti-cancer activity of DOX against cancer cells. Besides DOX delivery, GO nanomaterials are capable of loading anti-cancer agents and genetic tools to minimize drug resistance and enhance the cytolytic impact of DOX in cancer eradication. To enhance DOX accumulation, stimuli-responsive (redox-, light-, enzyme- and pH-sensitive) GO nanoparticles have been developed for DOX delivery. Development of targeted delivery of DOX-loaded GO nanomaterials against cancer cells may be achieved by surface modification of polymers such as polyethylene glycol, hyaluronic acid, and chitosan. DOX-loaded GO nanoparticles have demonstrated theranostic potential. Hybridization of GO with other nanocarriers such as silica and gold nanoparticles further broadens their potential anti-cancer therapy applications.

Dual relationship between long non-coding RNAs and STAT3 signaling in different cancers: New insight to proliferation and metastasis.

Uncontrolled growth and metastasis of cancer cells is an increasing challenge for overcoming cancer, and improving survival of patients. Complicated signaling networks account for proliferation and invasion of cancer cells that need to be elucidated for providing effective cancer therapy, and minimizing their malignancy. Long non-coding RNAs (lncRNAs) are RNA molecules with a length of more than 200 nucleotides. They participate in cellular events, and their dysregulation in a common phenomenon in different cancers. Noteworthy, lncRNAs can regulate different molecular pathways, and signal transducer and activator of transcription 3 (STAT3) is one of them. STAT3 is a tumor-promoting factors in cancers due to its role in cancer proliferation (cell cycle progression and apoptosis inhibition) and metastasis (EMT induction). LncRNAs can function as upstream mediators of STAT3 pathway, reducing/enhancing its expression. This dual relationship is of importance in affecting proliferation and metastasis of cancer cells. The response of cancer cells to therapy such as chemotherapy and radiotherapy is regulated by lncRNA/STAT3 axis. Tumor-promoting lncRNAs including NEAT1, SNHG3 and H19 induces STAT3 expression, while tumor-suppressing lncRNAs such as MEG3, PTCSC3 and NKILA down-regulate STAT3 expression. Noteworthy, upstream mediators of STAT3 such as microRNAs can be regulated by lncRNAs. These complicated signaling networks are mechanistically described in the current review.

Pre-clinical investigation of STAT3 pathway in bladder cancer: Paving the way for clinical translation.

Effective cancer therapy requires identification of signaling networks and investigating their potential role in proliferation and invasion of cancer cells. Among molecular pathways, signal transducer and activator of transcription 3 (STAT3) has been of importance due to its involvement in promoting proliferation, and invasion of cancer cells, and mediating chemoresistance. In the present review, our aim is to reveal role of STAT3 pathway in bladder cancer (BC), as one of the leading causes of death worldwide. In respect to its tumor-promoting role, STAT3 is able to enhance the growth of BC cells via inhibiting apoptosis and cell cycle arrest. STAT3 also contributes to metastasis of BC cells via upregulating of MMP-2 and MMP-9 as well as genes in the EMT pathway. BC cells obtain chemoresistance via STAT3 overexpression and its inhibition paves the way for increasing efficacy of chemotherapy. Different molecular pathways such as KMT1A, EZH2, DAB2IP and non-coding RNAs including microRNAs and long non-coding RNAs can function as upstream mediators of STAT3 that are discussed in this review article.

Cervical cancer progression is regulated by SOX transcription factors: Revealing signaling networks and therapeutic strategies.

Cervical cancer is the fourth common gynecologic cancer and is considered as second leading cause of death among women. Various strategies are applied in treatment of cervical cancer including radiotherapy, chemotherapy and surgery. However, cervical cancer cells demonstrate aggressive behavior in advanced phases, requiring novel strategies in their elimination. On the other hand, SOX proteins are transcription factors capable of regulating different molecular pathways and their expression varies during embryogenesis, disease development and carcinogenesis. In the present review, our aim is to reveal role of SOX transcription factors in cervical cancer. SOX transcription factors play like a double-edged sword in cancer. For instance, SOX9 possesses both tumor-suppressor and tumor-promoting role in cervical cancer. Therefore, exact role of each SOX members in cervical cancer has been discussed to direct further experiments for revealing other functions. SOX proteins can regulate proliferation and metastasis of cervical cancer cells. Furthermore, response of cervical cancer cells to chemotherapy and radiotherapy is tightly regulated by SOX transcription factors. Different downstream targets of SOX proteins such as Wnt signaling, EMT and Hedgehog have been identified. Besides, upstream mediators such as microRNAs, lncRNAs and circRNAs can regulate SOX expression in cervical cancer. In addition to pre-clinical studies, role of SOX transcription factors as prognostic and diagnostic tools in cervical cancer has been shown.

Employing siRNA tool and its delivery platforms in suppressing cisplatin resistance: Approaching to a new era of cancer chemotherapy.

Although chemotherapy is a first option in treatment of cancer patients, drug resistance has led to its failure, requiring strategies to overcome it. Cancer cells are capable of switching among molecular pathways to ensure their proliferation and metastasis, leading to their resistance to chemotherapy. The molecular pathways and mechanisms that are responsible for cancer progression and growth, can be negatively affected for providing chemosensitivity. Small interfering RNA (siRNA) is a powerful tool extensively applied in cancer therapy in both pre-clinical (in vitro and in vivo) and clinical studies because of its potential in suppressing tumor-promoting factors. As such oncogene pathways account for cisplatin (CP) resistance, their targeting by siRNA plays an important role in reversing chemoresistance. In the present review, application of siRNA for suppressing CP resistance is discussed. The first priority of using siRNA is sensitizing cancer cells to CP-mediated apoptosis via down-regulating survivin, ATG7, Bcl-2, Bcl-xl, and XIAP. The cancer stem cell properties and related molecular pathways including ID1, Oct-4 and nanog are inhibited by siRNA in CP sensitivity. Cell cycle arrest and enhanced accumulation of CP in cancer cells can be obtained using siRNA. In overcoming siRNA challenges such as off-targeting feature and degradation, carriers including nanoparticles and biological carriers have been applied. These carriers are important in enhancing cellular accumulation of siRNA, elevating gene silencing efficacy and reversing CP resistance.

The involvement of epithelial-to-mesenchymal transition in doxorubicin resistance: Possible molecular targets.

Considering the fact that cancer cells can switch among various molecular pathways and mechanisms to ensure their progression, chemotherapy is no longer effective enough in cancer therapy. As an anti-tumor agent, doxorubicin (DOX) is derived from Streptomyces peucetius and can induce cytotoxicity by binding to topoisomerase enzymes to suppress DNA replication, leading to apoptosis and cell cycle arrest. However, efficacy of DOX in suppressing cancer progression is restricted by development of drug resistance. Cancer cells elevate their metastasis in triggering DOX resistance. The epithelial-to-mesenchymal transition (EMT) mechanism participates in transforming epithelial cells into mesenchymal cells that have fibroblast-like features. The EMT diminishes intercellular adhesion and enhances migration of cells that are necessary for carcinogenesis. Various oncogenic molecular pathways stimulate EMT in cancer. EMT can induce DOX resistance, and in this way, upstream mediators such as ZEB proteins, microRNAs, Twist1 and TGF-ß play a significant role. Identification of molecular pathways involved in EMT regulation and DOX resistance has resulted in using gene therapy such as microRNA transfection and siRNA in overcoming chemoresistance. Furthermore, curcumin and formononetin, owing to their cytotoxicity against cancer cells, can suppress EMT in mediating DOX sensitivity. For promoting efficacy in DOX sensitivity, nanoparticles have been developed for boosting ability in EMT inhibition.

Pre-Clinical and Clinical Applications of Small Interfering RNAs (siRNA) and Co-Delivery Systems for Pancreatic Cancer Therapy.

Pancreatic cancer (PC) is one of the leading causes of death and is the fourth most malignant tumor in men. The epigenetic and genetic alterations appear to be responsible for development of PC. Small interfering RNA (siRNA) is a powerful genetic tool that can bind to its target and reduce expression level of a specific gene. The various critical genes involved in PC progression can be effectively targeted using diverse siRNAs. Moreover, siRNAs can enhance efficacy of chemotherapy and radiotherapy in inhibiting PC progression. However, siRNAs suffer from different off target effects and their degradation by enzymes in serum can diminish their potential in gene silencing. Loading siRNAs on nanoparticles can effectively protect them against degradation and can inhibit off target actions by facilitating targeted delivery. This can lead to enhanced efficacy of siRNAs in PC therapy. Moreover, different kinds of nanoparticles such as polymeric nanoparticles, lipid nanoparticles and metal nanostructures have been applied for optimal delivery of siRNAs that are discussed in this article. This review also reveals that how naked siRNAs and their delivery systems can be exploited in treatment of PC and as siRNAs are currently being applied in clinical trials, significant progress can be made by translating the current findings into the clinical settings.