Epigenetic regulation of autophagy by non-coding RNAs in gastrointestinal tumors: Biological functions and therapeutic perspectives.

Cancer is the manifestation of changes and mutations in genetic and epigenetic levels. Non-coding RNAs (ncRNAs) are commonly dysregulated in disease pathogenesis, and their role in cancer has been well-documented. The ncRNAs regulate various molecular pathways and mechanisms in cancer that can lead to induction/inhibition of carcinogenesis. Autophagy is a molecular "self-digestion" mechanism its function can be pro-survival or pro-death in tumor cells. The aim of the present review is to evaluate the role of ncRNAs in regulating autophagy in gastrointestinal tumors. The role of the ncRNA/autophagy axis in affecting the progression of gastric, liver, colorectal, pancreatic, esophageal, and gallbladder cancers is investigated. Both ncRNAs and autophagy mechanisms can function as oncogenic or onco-suppressor and this interaction can determine the growth, invasion, and therapy response of gastrointestinal tumors. ncRNA/autophagy axis can reduce/increase the proliferation of gastrointestinal tumors via the glycolysis mechanism. Furthermore, related molecular pathways of metastasis, such as EMT and MMPs, are affected by the ncRNA/autophagy axis. The response of gastrointestinal tumors to chemotherapy and radiotherapy can be suppressed by pro-survival autophagy, and ncRNAs are essential regulators of this mechanism. miRNAs can regulate related genes and proteins of autophagy, such as ATGs and Beclin-1. Furthermore, lncRNAs and circRNAs down-regulate miRNA expression via sponging to modulate the autophagy mechanism. Moreover, anti-cancer agents can affect the expression level of ncRNAs regulating autophagy in gastrointestinal tumors. Therefore, translating these findings into clinics can improve the prognosis of patients.

Biological impact and therapeutic perspective of targeting PI3K/Akt signaling in hepatocellular carcinoma: Promises and Challenges.

Cancer progression results from activation of various signaling networks. Among these, PI3K/Akt signaling contributes to proliferation, invasion, and inhibition of apoptosis. Hepatocellular carcinoma (HCC) is a primary liver cancer with high incidence rate, especially in regions with high prevalence of viral hepatitis infection. Autoimmune disorders, diabetes mellitus, obesity, alcohol consumption, and inflammation can also lead to initiation and development of HCC. The treatment of HCC depends on the identification of oncogenic factors that lead tumor cells to develop resistance to therapy. The present review article focuses on the role of PI3K/Akt signaling in HCC progression. Activation of PI3K/Akt signaling promotes glucose uptake, favors glycolysis and increases tumor cell proliferation. It inhibits both apoptosis and autophagy while promoting HCC cell survival. PI3K/Akt stimulates epithelial-to-mesenchymal transition (EMT) and increases matrix-metalloproteinase (MMP) expression during HCC metastasis. In addition to increasing colony formation capacity and facilitating the spread of tumor cells, PI3K/Akt signaling stimulates angiogenesis. Therefore, silencing PI3K/Akt signaling prevents aggressive HCC cell behavior. Activation of PI3K/Akt signaling can confer drug resistance, particularly to sorafenib, and decreases the radio-sensitivity of HCC cells. Anti-cancer agents, like phytochemicals and small molecules can suppress PI3K/Akt signaling by limiting HCC progression. Being upregulated in tumor tissues and clinical samples, PI3K/Akt can also be used as a biomarker to predict patients' response to therapy.

The protective impact of curcumin, vitamin D and E along with manganese oxide and Iron (III) oxide nanoparticles in rats with scrotal hyperthermia: Role of apoptotic genes, miRNA and circRNA.

BACKGROUND: Infertility is one of the major factors affecting most people around the world. Short-term exposure to high temperatures can cause hyperthermia, which is one of the causes of male infertility. The aim of this study was to investigate the protective effect of curcumin, vitamins D and E along with Iron (III) oxide nanoparticles (Fe2O3-NPs) and manganese oxide nanoparticles (MnO2-NPs) on semen parameters and its effect on miRNA21 and circRNA0001518 expression. MATERIAL AND METHODS: In this study, the lower part of the rat was exposed to 43 °C for 5 weeks every other day for 5 weeks. Then the animals were killed. Tissue samples were collected for sperm parameters analysis, and tissue samples were taken for evaluation of apoptosis levels in germ cells, and RNA extraction in order to examine the expression of Bax, Bcl-2, miRNA, and CircRNA genes. RESULTS: The results of this study showed that administration of curcumin, vitamin D, and vitamin E with Fe2O3-NPs and MnO2-NPs can improve the parameters of semen, Bax gene expression, Bcl-2 as well as miRNA and CircRNA in rats with testicular hyperthermia. In addition, curcumin by reducing the toxicity of Fe2O3 nanoparticles was able to reduce its negative effects and also reduce apoptosis in germ cells. This decrease in apoptosis was attributed to decreased Bcl-2 gene expression and increased expression of Bax, miRNA-21, and circRNA0001518. CONCLUSION: All the results of this study confirmed that Fe2O3-NPs and Mno2-NPs containing antioxidants or vitamins are useful in improving fertility in rats due to scrotal hyperthermia. Although Fe2O3-NPs and Mno2-NPs containing both antioxidants and vitamins had a greater effect on improving fertility and reducing the toxic effects of nanoparticles.

Curcumin in treatment of hematological cancers: Promises and challenges.

Hematological cancers include leukemia, myeloma and lymphoma and up to 178.000 new cases are diagnosed with these tumors each year. Different kinds of treatment including radiotherapy, chemotherapy, immunotherapy and stem cell transplantation have been employed in the therapy of hematological cancers. However, they are still causing death among patients. On the other hand, curcumin as an anti-cancer agent for the suppression of human cancers has been introduced. The treatment of hematological cancers using curcumin has been followed. Curcumin diminishes viability and survival rate of leukemia, myeloma and lymphoma cells. Curcumin stimulates apoptosis and G2/M arrest to impair progression of tumor. Curcumin decreases levels of matrix metalloproteinases in suppressing cancer metastasis. A number of downstream targets including VEGF, Akt and STAT3 undergo suppression by curcumin in suppressing progression of hematological cancers. Curcumin stimulates DNA damage and reduces resistance of cancer cells to irradiation. Furthermore, curcumin causes drug sensitivity of hematological tumors, especially myeloma. For targeted delivery of curcumin and improving its pharmacokinetic and anti-cancer features, nanostructures containing curcumin and other anti-cancer agents have been developed.

EZH2 as a potential therapeutic target for gastrointestinal cancers.

Gastrointestinal (GI) cancers continue to be a major cause of mortality and morbidity globally. Understanding the molecular pathways associated with cancer progression and severity is essential for creating effective cancer treatments. In cancer research, there is a notable emphasis on Enhancer of zeste homolog 2 (EZH2), a key player in gene expression influenced by its irregular expression and capacity to attach to promoters and alter methylation status. This review explores the impact of EZH2 signaling on various GI cancers, such as colorectal, gastric, pancreatic, hepatocellular, esophageal, and cholangiocarcinoma. The primary function of EZH2 signaling is to facilitate the accelerated progression of cancer cells. Additionally, EZH2 has the capacity to modulate the reaction of GI cancers to chemotherapy and radiotherapy. Numerous pathways, including long non-coding RNAs and microRNAs, serve as upstream regulators of EZH2 in these types of cancer. EZH2's enzymatic activity enables it to attach to target gene promoters, resulting in methylation that modifies their expression. EZH2 could be considered as an independent prognostic factor, with increased expression correlating with a worse disease prognosis. Additionally, a range of gene therapies including small interfering RNA, and anti-tumor agents are being explored to target EZH2 for cancer treatment. This comprehensive review underscores the current insights into EZH2 signaling in gastrointestinal cancers and examines the prospect of therapies targeting EZH2 to enhance patient outcomes.

Nanoliposomes as nonviral vectors in cancer gene therapy.

Nonviral vectors, such as liposomes, offer potential for targeted gene delivery in cancer therapy. Liposomes, composed of phospholipid vesicles, have demonstrated efficacy as nanocarriers for genetic tools, addressing the limitations of off-targeting and degradation commonly associated with traditional gene therapy approaches. Due to their biocompatibility, stability, and tunable physicochemical properties, they offer potential in overcoming the challenges associated with gene therapy, such as low transfection efficiency and poor stability in biological fluids. Despite these advancements, there remains a gap in understanding the optimal utilization of nanoliposomes for enhanced gene delivery in cancer treatment. This review delves into the present state of nanoliposomes as carriers for genetic tools in cancer therapy, sheds light on their potential to safeguard genetic payloads and facilitate cell internalization alongside the evolution of smart nanocarriers for targeted delivery. The challenges linked to their biocompatibility and the factors that restrict their effectiveness in gene delivery are also discussed along with exploring the potential of nanoliposomes in cancer gene therapy strategies by analyzing recent advancements and offering future directions.

The pharmacological and biological importance of EZH2 signaling in lung cancer.

Up to 18% of cancer-related deaths worldwide are attributed to lung tumor and global burden of this type of cancer is ascending. Different factors are responsible for development of lung cancer such as smoking, environmental factors and genetic mutations. EZH2 is a vital protein with catalytic activity and belongs to PCR2 family. EZH2 has been implicated in regulating gene expression by binding to promoter of targets. The importance of EZH2 in lung cancer is discussed in current manuscript. Activation of EZH2 significantly elevates the proliferation rate of lung cancer. Furthermore, metastasis and associated molecular mechanisms including EMT undergo activation by EZH2 in enhancing the lung cancer progression. The response of lung cancer to therapy can be significantly diminished due to EZH2 upregulation. Since EZH2 increases tumor progression, anti-cancer agents suppressing its expression reduce malignancy. In spite of significant effort in understanding modulatory function of EZH2 on other pathways, it appears that EZH2 can be also regulated and controlled by other factors that are described in current review. Therefore, translating current findings to clinic can improve treatment and management of lung cancer patients.

Non-coding RNAs and exosomal ncRNAs in multiple myeloma: An emphasis on molecular pathways.

One of the most common hematological malignancies is multiple myeloma (MM) that its mortality and morbidity have increased. The incidence rate of MM is suggested to be higher in Europe and various kinds of therapeutic strategies including stem cell transplantation. However, MM treatment is still challenging and gene therapy has been shown to be promising. The non-coding RNAs (ncRNAs) including miRNAs, lncRNAs and circRNAs are considered as key players in initiation, development and progression of MM. In the present review, the role of ncRNAs in MM progression and drug resistance is highlighted to provide new insights for future experiments for their targeting and treatment of MM. The miRNAs affect proliferation and invasion of MM cells, and targeting tumor-promoting miRNAs can induce apoptosis and cell cycle arrest, and reduces proliferation of MM cells. Furthermore, miRNA regulation is of importance for modulating metastasis and chemotherapy response of tumor cells. The lncRNAs exert the same function and determine proliferation, migration and therapy response of MM cells. Notably, lncRNAs mainly target miRNAs in regulating MM progression. The circRNAs also target different molecular pathways in regulating MM malignancy that miRNAs are the most well-known ones. Furthermore, clinical application of ncRNAs in MM is discussed.

siRNA and targeted delivery systems in breast cancer therapy.

Recently, nucleic acid drugs have been considered as promising candidates in treatment of various diseases, especially cancer. Because of developing resistance to conventional chemotherapy, use of genetic tools in cancer therapy appears inevitable. siRNA is a RNAi tool with capacity of suppressing target gene. Owing to overexpression of oncogenic factors in cancer, siRNA can be used for suppressing those pathways. This review emphasizes the function of siRNA in treatment of breast tumor. The anti-apoptotic-related genes including Bcl-2, Bcl-xL and survivin can be down-regulated by siRNA in triggering cell death in breast cancer. STAT3, STAT8, Notch1, E2F3 and NF-κB are among the factors with overexpression in breast cancer that their silencing by siRNA paves the way for impairing tumor proliferation and invasion. The oncogenic mechanisms in drug resistance development in breast tumor such as lncRNAs can be suppressed by siRNA. Furthermore, siRNA reducing P-gp activity can increase drug internalization in tumor cells. Because of siRNA degradation at bloodstream and low accumulation at tumor site, nanoplatforms have been employed for siRNA delivery to suppress breast tumor progression via improving siRNA efficacy in gene silencing. Development of biocompatible and efficient nanostructures for siRNA delivery can make milestone progress in alleviation of breast cancer patients.

Towards dual function of autophagy in breast cancer: A potent regulator of tumor progression and therapy response.

As a devastating disease, breast cancer has been responsible for decrease in life expectancy of females and its morbidity and mortality are high. Breast cancer is the most common tumor in females and its treatment has been based on employment of surgical resection, chemotherapy and radiotherapy. The changes in biological behavior of breast tumor relies on genomic and epigenetic mutations and depletions as well as dysregulation of molecular mechanisms that autophagy is among them. Autophagy function can be oncogenic in increasing tumorigenesis, and when it has pro-death function, it causes reduction in viability of tumor cells. The carcinogenic function of autophagy in breast tumor is an impediment towards effective therapy of patients, as it can cause drug resistance and radio-resistance. The important hallmarks of breast tumor such as glucose metabolism, proliferation, apoptosis and metastasis can be regulated by autophagy. Oncogenic autophagy can inhibit apoptosis, while it promotes stemness of breast tumor. Moreover, autophagy demonstrates interaction with tumor microenvironment components such as macrophages and its level can be regulated by anti-tumor compounds in breast tumor therapy. The reasons of considering autophagy in breast cancer therapy is its pleiotropic function, dual role (pro-survival and pro-death) and crosstalk with important molecular mechanisms such as apoptosis. Moreover, current review provides a pre-clinical and clinical evaluation of autophagy in breast tumor.

STAT3 signaling in prostate cancer progression and therapy resistance: An oncogenic pathway with diverse functions.

The categorization of cancers demonstrates that prostate cancer is the most common malignancy in men and it causes high death annually. Prostate cancer patients are diagnosed mainly via biomarkers such as PSA test and patients show poor prognosis. Prostate cancer cells rapidly diffuse into different parts of body and their metastasis is also a reason for death. Current therapies for prostate cancer patients include chemotherapy, surgery and radiotherapy as well as targeted therapy. The progression of prostate cancer cells is regulated by different factors that STAT3 signaling is among them. Growth factors and cytokines such as IL-6 can induce STAT3 signaling and it shows carcinogenic impact. Activation of STAT3 signaling occurs in prostate cancer and it promotes malignant behavior of tumor cells. Induction of STAT3 signaling increases glycolysis and proliferation of prostate cancer cells and prevents apoptosis. Furthermore, STAT3 signaling induces EMT mechanism in increasing cancer metastasis. Activation of STAT3 signaling stimulates drug resistance and the limitation of current works is lack of experiment related to role of STAT3 signaling in radio-resistance in prostate tumor. Calcitriol, capsazepine and ß-elemonic are among the compounds capable of targeting STAT3 signaling and its inhibition in prostate cancer therapy. In addition to natural products, small molecules targeting STAT3 signaling have been developed in prostate cancer therapy.

Advances in RNAi therapies for gastric cancer: Targeting drug resistance and nanoscale delivery.

Gastric cancer poses a significant health challenge, and exploring innovative therapeutic strategies is imperative. RNA interference (RNAi) has employed as an important therapeutic strategy for diseases by selectively targeting key pathways involved in diseases pathogenesis. Small interfering RNA (siRNA), a potent RNAi tool, possesses the capability to silence genes and downregulate their expression. This review provides a comprehensive examination of the potential applications of small interfering RNA (siRNA) and short hairpin RNA (shRNA), supplemented by an in-depth analysis of nanoscale delivery systems, in the context of gastric cancer treatment. The potential of siRNA to markedly diminish the proliferation and invasion of gastric cancer cells through the modulation of critical molecular pathways, including PI3K, Akt, and EMT, is highlighted. Besides, siRNA demonstrates its efficacy in inducing chemosensitivity in gastric tumor cells, thus impeding tumor progression. However, the translational potential of unmodified siRNA faces challenges, particularly in vivo and during clinical trials. To address this, we underscore the pivotal role of nanostructures in facilitating the delivery of siRNA to gastric cancer cells, effectively suppressing their progression and enhancing gene silencing efficiency. These siRNA-loaded nanoparticles exhibit robust internalization into gastric cancer cells, showcasing their potential to significantly reduce tumor progression. The translation of these findings into clinical trials holds promise for advancing the treatment of gastric cancer patients.

miRNAs as short non-coding RNAs in regulating doxorubicin resistance.

The treatment of cancer patients has been prohibited by chemoresistance. Doxorubicin (DOX) is an anti-tumor compound disrupting proliferation and triggering cell cycle arrest via inhibiting activity of topoisomerase I and II. miRNAs are endogenous RNAs localized in cytoplasm to reduce gene level. Abnormal expression of miRNAs changes DOX cytotoxicity. Overexpression of tumor-promoting miRNAs induces DOX resistance, while tumor-suppressor miRNAs inhibit DOX resistance. The miRNA-mediated regulation of cell death and hallmarks of cancer can affect response to DOX chemotherapy in tumor cells. The transporters such as P-glycoprotein are regulated by miRNAs in DOX chemotherapy. Upstream mediators including lncRNAs and circRNAs target miRNAs in affecting capacity of DOX. The response to DOX chemotherapy can be facilitated after administration of agents that are mostly phytochemicals including curcumol, honokiol and ursolic acid. These agents can regulate miRNA expression increasing DOX's cytotoxicity. Since delivery of DOX alone or in combination with other drugs and genes can cause synergistic impact, the nanoparticles have been introduced for drug sensitivity. The non-coding RNAs determine the response of tumor cells to doxorubicin chemotherapy. microRNAs play a key role in this case and they can be sponged by lncRNAs and circRNAs, showing interaction among non-coding RNAs in the regulation of doxorubicin sensitivity.

Graphene oxide nanoarchitectures in cancer biology: Nano-modulators of autophagy and apoptosis.

Nanotechnology is a growing field, with many potential biomedical applications of nanomedicine for the treatment of different diseases, particularly cancer, on the horizon. Graphene oxide (GO) nanoparticles can act as carbon-based nanocarriers with advantages such as a large surface area, good mechanical strength, and the capacity for surface modification. These nanostructures have been extensively used in cancer therapy for drug and gene delivery, photothermal therapy, overcoming chemotherapy resistance, and for imaging procedures. In the current review, we focus on the biological functions of GO nanoparticles as regulators of apoptosis and autophagy, the two major forms of programmed cell death. GO nanoparticles can either induce or inhibit autophagy in cancer cells, depending on the conditions. By stimulating autophagy, GO nanocarriers can promote the sensitivity of cancer cells to chemotherapy. However, by impairing autophagy flux, GO nanoparticles can reduce cell survival and enhance inflammation. Similarly, GO nanomaterials can increase ROS production and induce DNA damage, thereby sensitizing cancer cells to apoptosis. In vitro and in vivo experiments have investigated whether GO nanomaterials show any toxicity in major body organs, such as the brain, liver, spleen, and heart. Molecular pathways, such as ATG, MAPK, JNK, and Akt, can be regulated by GO nanomaterials, leading to effects on autophagy and apoptosis. These topics are discussed in this review to shed some lights towards the biomedical potential of GO nanoparticles and their biocompatibility, paving the way for their future application in clinical trials.

New emerging targets in osteosarcoma therapy: PTEN and PI3K/Akt crosstalk in carcinogenesis.

Osteosarcoma (OS) is a malignant bone carcinoma that affects people in childhood and adulthood. The heterogeneous nature and chromosomal instability represent certain characteristics of OS cells. These cancer cells grow and migrate abnormally, making the prognosis undesirable for patients. Conventional and current treatments fail to completely eradicate tumor cells, so new therapeutics targeting genes may be considered. PI3K/Akt is a regulator of events such as growth, cell death, migration, and differentiation, and its expression changes during cancer progression. PTEN reduces PI3K/Akt expression, and its mutations and depletions have been reported in various tumors. Experimental evidence shows that there is upregulation of PI3K/Akt and downregulation of PTEN in OS. Increasing PTEN expression may suppress PI3K/Akt to minimize tumorigenesis. In addition, PI3K/Akt shows a positive association with growth, metastasis, EMT and metabolism of OS cells and inhibits apoptosis. Importantly, overexpression of PI3K/Akt causes drug resistance and radio-resistance and its level can be modulated by miRNAs, lncRNAs and circRNAs. Silencing PI3K/Akt by compounds and drugs can suppress OS. Here, we review in detail the function of the PTEN/PI3K/Akt in OS, revealing its biological function, function in tumor progression, resistance to therapy, and pharmacological significance.

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.

Transforming growth factor-beta (TGF-ß) in prostate cancer: A dual function mediator?

Transforming growth factor-beta (TGF-ß) is a member of a family of secreted cytokines with vital biological functions in cells. The abnormal expression of TGF-ß signaling is a common finding in pathological conditions, particularly cancer. Prostate cancer (PCa) is one of the leading causes of death among men. Several genetic and epigenetic alterations can result in PCa development, and govern its progression. The present review attempts to shed some light on the role of TGF-ß signaling in PCa. TGF-ß signaling can either stimulate or inhibit proliferation and viability of PCa cells, depending on the context. The metastasis of PCa cells is increased by TGF-ß signaling via induction of EMT and MMPs. Furthermore, TGF-ß signaling can induce drug resistance of PCa cells, and can lead to immune evasion via reducing the anti-tumor activity of cytotoxic T cells and stimulating regulatory T cells. Upstream mediators such as microRNAs and lncRNAs, can regulate TGF-ß signaling in PCa. Furthermore, some pharmacological compounds such as thymoquinone and valproic acid can suppress TGF-ß signaling for PCa therapy. TGF-ß over-expression is associated with poor prognosis in PCa patients. Furthermore, TGF-ß up-regulation before prostatectomy is associated with recurrence of PCa. Overall, current review discusses role of TGF-ß signaling in proliferation, metastasis and therapy response of PCa cells and in order to improve knowledge towards its regulation, upstream mediators of TGF-ß such as non-coding RNAs are described. Finally, TGF-ß regulation and its clinical application are discussed.

Targeting AMPK signaling in ischemic/reperfusion injury: From molecular mechanism to pharmacological interventions.

Ischemia is a pathological process in which blood supply to a particular organ is temporarily interrupted resulting in disturbed biological function and homeostasis of local tissues. Following ischemia, reperfusion and reoxygenation may occur which further worsens oxidative stress-mediated damage in cells and tissues. The combined processes are referred to as ischemia/reperfusion (I/R) injury. Immediate management and treatment of I/R is of utmost importance for preventing irreversible and extensive cellular damage. Apoptosis, inflammation and oxidative stress are the most validated pathologies associated with I/R. AMP-activated protein kinase (AMPK) modulates energy metabolism in cells and its activation occurs in response to elevated AMP and ADP levels. Aberrant levels of AMPK are noted in various pathological settings such as diabetes mellitus, cancer and neurological diseases. This review emphasizes AMPK signaling, its related molecular pathways and therapeutic utility during I/R. Activation of AMPK through phosphorylation prevents apoptosis and reduces oxidative stress and inflammation upon I/R. Inducing AMPK signaling normalizes mitochondrial function to inhibit cell death. Autophagy as a cytoprotective mechanism undergoes activation by AMPK/mTOR and AMPK/ULK1 pathways. AMPK reinforces the antioxidant defense capacity via Nrf2 signaling to counteract oxidative stress in I/R. Protective compounds including phytochemicals activate AMPK to alleviate I/R injury.

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.

Overcoming doxorubicin resistance in cancer: siRNA-loaded nanoarchitectures for cancer gene therapy.

Gene therapy can be used as a cancer therapy by affecting signaling networks participating in the aggressive behavior of tumors. Small interfering RNA (siRNA) is a genetic tool employed for gene silencing. The siRNA molecules have a length of 21-22 nucleotides, and are synthetic, short non-coding RNAs. The siRNA molecule should be loaded into the RISC complex to carry out its function to degrade mRNA and reduce protein expression. By targeting oncogenic pathways, siRNA can also promote chemosensitivity and reduce resistance. Doxorubicin (DOX) is an anthracycline family member capable of triggering cell cycle arrest via binding to topoisomerase II and inhibiting DNA replication. The present review focuses on the design of siRNA for increasing DOX sensitivity and overcoming resistance. Molecular pathways such as STAT3, Notch1, Mcl-1 and Nrf2 can be down-regulated by siRNA to promote DOX sensitivity. Furthermore, siRNA can be used to suppress the activity of P-glycoprotein as a cell membrane transporter of drugs, leading to enhanced accumulation of DOX. The co-delivery of DOX and siRNA both incorporated into nanoparticles can increase the intracellular accumulation in cancer cells, and protect siRNA against degradation by enzymes. Furthermore, the circulation time of DOX is lengthened to boost cytotoxicity against cancer cells. The surface modification of nanocarriers with ligands such as RGD or folate increases their selectivity towards cancer cells. Moreover, smart nanostructures, including pH-, redox- and light-responsive are optimized for siRNA and DOX delivery and tumor treatment.