Potential Therapeutic Targets of Resveratrol,a Plant Polyphenol,and Its Role in the Therapy of Various Types of Cancer

Cancer is among the most prominent causes of mortality worldwide. Different cancer therapy modes employed, including chemotherapy and radiotherapy, have been reported to be significant in cancer management, but the side effects associated with these treatment strategies are still a health problem. Therefore, alternative anticancer drugs based on medicinal plants or their active compounds have been generating attention because of their less serious side effects. Medicinal plants are an excellent source of phytochemicals that have been recognized to have health-prompting effects through modulating cell signaling pathways. Resveratrol is a well-known polyphenolic molecule with antioxidant, anti-inflammatory, and health-prompting effects among which its anticancer role has been best defined. Additionally, this polyphenol has confirmed its role in cancer management because it activates tumor suppressor genes, suppresses cell proliferation, induces apoptosis, inhibits angiogenesis, and modulates several other cell signaling molecules. The anticancer potential of resveratrol is recognized in numerous in vivo and in vitro studies. Previous experimental data suggested that resveratrol may be valuable in cancer management or improve the efficacy of drugs when given with anticancer drugs. This review emphasizes the potential role of resveratrol as an anticancer drug by modulating numerous cells signaling pathways in different types of cancer.     

Photodynamic Therapy and Immune Checkpoint Blockade†

Immune checkpoints including PD-1 and CTLA-4 help to regulate the intensity and timeframe of the immune response. Since they become upregulated in cancer and prevent sufficient antitumor immunity, monoclonal antibodies against these checkpoints have shown clinical promise for a range of cancers. Multimodal treatment plans combining immune checkpoint inhibitors with other therapies, including photodynamic therapy (PDT), may help to expand treatment efficacy and minimize side effects. PDT's cytotoxic effects are spatially limited by the light activation process, constraining PDT direct effects to the treatment field. The production of damage-associated molecular patterns and tumor-associated antigens from PDT can encourage accumulation and maturation of antigen-presenting cells and reprogram the tumor microenvironment to be more susceptible to therapies targeting immune checkpoints.     

高分子材料调控肿瘤免疫微环境的研究进展

随着肿瘤免疫疗法在临床应用取得巨大突破,通过抗肿瘤免疫反应提高抗肿瘤疗效的治疗方式受到了广泛的关注.然而,肿瘤组织存在复杂的免疫抑制性微环境,严重限制了部分免疫疗法的效果.长期以来,高分子材料作为重要的药物递送载体受到广泛关注,但是其在调控肿瘤免疫微环境的功能及应用方面尚未引起足够的重视.在本文中,我们一方面介绍了肿瘤组织形成免疫抑制性微环境的成因,如肿瘤组织存在多种免疫抑制性细胞,如调节性T细胞(Tregs)、髓系来源抑制性细胞(MDSCs)和肿瘤相关巨噬细胞(TAMs)等,以及免疫细胞、肿瘤细胞等分泌的大量细胞因子、趋化因子、代谢产物等.另一方面,重点介绍了近年来高分子材料作为载体递送免疫调节分子或发挥自身免疫调节功能,调控或逆转免疫抑制性微环境的策略和典型代表,证明了高分子材料在调控肿瘤免疫微环境,改善肿瘤治疗效果方面的巨大潜力.     

Application of nanomaterials in cancer immunotherapy

Cancer has become one of the major public health problems all over the word. Cancer immunotherapy is the treatment that utilizing the patient's own immune system to fight cancer. Although promising outcomes of cancer immunotherapy have been achieved nowadays, it is still a challenge to develop a therapeutic pattern with low toxicities, high specificity, and long-lasting efficacy in this field. Nanomaterials can be employed as vehicles to deliver antigens or immune modulating therapeutics. Nanomaterials can enhance the efficacy of cancer immunotherapy by protecting their payload during circulation, promoting the delivery of antigen to antigen presenting cell, triggering the activation of antigen-specific T cell, and regulating the immunosuppressive tumor microenvironment. In this review, we briefly summarize the application of nanomaterials in cancer immunotherapy, including nanovaccines, tumor immune environment modulation, and other application. Without a doubt, with the advances of the interdisciplinary research focused for materials science, immunology and tumor biology, cancer immunotherapy will further enhance the therapeutic benefits and reduce side effects in the future.     

From Oncogenic Signaling Pathways to Single-Cell Sequencing of Immune Cells: Changing the Landscape of Cancer Immunotherapy

Over the past decade, there have been remarkable advances in understanding the signaling pathways involved in cancer development. It is well-established that cancer is caused by the dysregulation of cellular pathways involved in proliferation, cell cycle, apoptosis, cell metabolism, migration, cell polarity, and differentiation. Besides, growing evidence indicates that extracellular matrix signaling, cell surface proteoglycans, and angiogenesis can contribute to cancer development. Given the genetic instability and vast intra-tumoral heterogeneity revealed by the single-cell sequencing of tumoral cells, the current approaches cannot eliminate the mutating cancer cells. Besides, the polyclonal expansion of tumor-infiltrated lymphocytes in response to tumoral neoantigens cannot elicit anti-tumoral immune responses due to the immunosuppressive tumor microenvironment. Nevertheless, the data from the single-cell sequencing of immune cells can provide valuable insights regarding the expression of inhibitory immune checkpoints/related signaling factors in immune cells, which can be used to select immune checkpoint inhibitors and adjust their dosage. Indeed, the integration of the data obtained from the single-cell sequencing of immune cells with immune checkpoint inhibitors can increase the response rate of immune checkpoint inhibitors, decrease the immune-related adverse events, and facilitate tumoral cell elimination. This study aims to review key pathways involved in tumor development and shed light on single-cell sequencing. It also intends to address the shortcomings of immune checkpoint inhibitors, i.e., their varied response rates among cancer patients and increased risk of autoimmunity development, via applying the data from the single-cell sequencing of immune cells.     

The Role and Regulation of Thromboxane A2 Signaling in Cancer-Trojan Horses and Misdirection

Over the last two decades, there has been an increasing awareness of the role of eicosanoids in the development and progression of several types of cancer, including breast, prostate, lung, and colorectal cancers. Several processes involved in cancer development, such as cell growth, migration, and angiogenesis, are regulated by the arachidonic acid derivative thromboxane A₂ (TXA₂). Higher levels of circulating TXA₂ are observed in patients with multiple cancers, and this is accompanied by overexpression of TXA₂ synthase (TBXAS1, TXA₂S) and/or TXA₂ receptors (TBXA2R, TP). Overexpression of TXA₂S or TP in tumor cells is generally associated with poor prognosis, reduced survival, and metastatic disease. However, the role of TXA₂ signaling in the stroma during oncogenesis has been underappreciated. TXA₂ signaling regulates the tumor microenvironment by modulating angiogenic potential, tumor ECM stiffness, and host immune response. Moreover, the by-products of TXA₂S are highly mutagenic and oncogenic, adding to the overall phenotype where TXA₂ synthesis promotes tumor formation at various levels. The stability of synthetic enzymes and receptors in this pathway in most cancers (with few mutations reported) suggests that TXA₂ signaling is a viable target for adjunct therapy in various tumors to reduce immune evasion, primary tumor growth, and metastasis.     

Cancer Cell-targeted and Activatable Photoimmunotherapy Spares T Cells in a 3D Coculture Model

Photodynamic therapy (PDT) is an established therapeutic modality that uses nonionizing near-infrared light to activate photocytotoxicity of endogenous or exogenous photosensitizers (PSs). An ongoing avenue of cancer research involves leveraging PDT to stimulate antitumor immune responses; however, these effects appear to be best elicited in low-dose regimens that do not provide significant tumor reduction using conventional, nonspecific PSs. The loss of immune enhancement at higher PDT doses may arise in part from indiscriminate damage to local immune cell populations, including tumor-infiltrating T cells. We previously introduced “tumor-targeted, activatable photoimmunotherapy” (taPIT) using molecular-targeted and cell-activatable antibody–PS conjugates to realize precision tumor photodamage with microscale fidelity. Here, we investigate the immune cell sparing effect provided by taPIT in a 3D model of the tumor immune microenvironment. We report that high-dose taPIT spares 25% of the local immune cell population, five times more than the conventional PDT regimen, in a 3D coculture model incorporating epithelial ovarian cancer cells and T cells. These findings suggest that the enhanced selectivity of taPIT may be utilized to achieve local tumor reduction with sparing of intratumor effector immune cells that would otherwise be lost if treated with conventional PDT.     

基于天然产物的铂类和芳基金属抗癌药物研究进展

临床使用的现代药物超过50%都来自于天然产物,它们不仅能够通过阻止细胞周期进程、抑制癌细胞存活信号通路以及调节免疫细胞等多种生物途径来阻止肿瘤生长及其进程,而且对正常组织表现出较低的毒性。虽然以顺铂为代表的金属抗肿瘤药物广泛用于临床,但是它们存在严重的耐药性和毒副作用,包括肾毒性、神经毒性等。因此,利用天然产物中的优势来改造铂类配合物,有望开发出新型铂类抗癌药物以克服铂药的缺陷。另一方面,芳基金属配合物因其良好的水溶性和对正常组织的低毒性受到了广泛关注,将天然产物与芳基金属配合物相结合,也为开发高效低毒的新型抗癌药物提供了更多可能。结合天然产物和金属各自优势开发基于天然产物的金属配合物作为抗癌剂已成为研究热点,开辟了抗癌的新途径。本文对已经报道的有关天然产物的铂类和芳基金属配合物的研究及作用机理进行了较为全面的综述,并对该领域的未来发展进行了展望。     

The updated role of exosomal proteins in the diagnosis,prognosis, and treatment of cancer

Exosomes are vesicles encompassed by a lipid bilayer that are released by various living cells. Exosomal proteins are encapsulated within the membrane or embedded on the surface. As an important type of exosome cargo, exosomal proteins can reflect the physiological status of the parent cell and play an essential role in cell–cell communication. Exosomal proteins can regulate tumor development, including tumor-related immune regulation, microenvironment reconstruction, angiogenesis, epithelial–mesenchymal transition, metastasis, etc. The features of exosomal proteins can provide insight into exosome generation, targeting, and biological function and are potential sources of markers for cancer diagnosis, prognosis, and treatment. Here, we summarize the effects of exosomal proteins on cancer biology, the latest progress in the application of exosomal proteins in cancer diagnosis and prognosis, and the potential contribution of exosomal proteins in cancer therapeutics and vaccines.Subject terms: Protein-protein interaction networks, Cancer microenvironment     

Natural Products Targeting the Mitochondria in Cancers

There are abundant sources of anticancer drugs in nature that have a broad prospect in anticancer drug discovery. Natural compounds, with biological activities extracted from plants and marine and microbial metabolites, have significant antitumor effects, but their mechanisms are various. In addition to providing energy to cells, mitochondria are involved in processes, such as cell differentiation, cell signaling, and cell apoptosis, and they have the ability to regulate cell growth and cell cycle. Summing up recent data on how natural products regulate mitochondria is valuable for the development of anticancer drugs. This review focuses on natural products that have shown antitumor effects via regulating mitochondria. The search was done in PubMed, Web of Science, and Google Scholar databases, over a 5-year period, between 2015 and 2020, with a keyword search that focused on natural products, natural compounds, phytomedicine, Chinese medicine, antitumor, and mitochondria. Many natural products have been studied to have antitumor effects on different cells and can be further processed into useful drugs to treat cancer. In the process of searching for valuable new drugs, natural products such as terpenoids, flavonoids, saponins, alkaloids, coumarins, and quinones cover the broad space.     

Curcumin and Resveratrol Improve Muscle Function and Structure through Attenuation of Proteolytic Markers in Experimental Cancer-Induced Cachexia

Muscle wasting and cachexia are prominent comorbidities in cancer. Treatment with polyphenolic compounds may partly revert muscle wasting. We hypothesized that treatment with curcumin or resveratrol in cancer cachectic mice may improve muscle phenotype and total body weight through attenuation of several proteolytic and signaling mechanisms in limb muscles. In gastrocnemius and soleus muscles of cancer cachectic mice (LP07 adenocarcinoma cells, N = 10/group): (1) LC-induced cachexia, (2) LC-cachexia+curcumin, and (3) LC-cachexia + resveratrol, muscle structure and damage (including blood troponin I), sirtuin-1, proteolytic markers, and signaling pathways (NF-κB and FoxO3) were explored (immunohistochemistry and immunoblotting). Compared to nontreated cachectic mice, in LC-cachexia + curcumin and LC-cachexia + resveratrol groups, body and muscle weights (gastrocnemius), limb muscle strength, muscle damage, and myofiber cross-sectional area improved, and in both muscles, sirtuin-1 increased, while proteolysis (troponin I), proteolytic markers, and signaling pathways were attenuated. Curcumin and resveratrol elicited beneficial effects on fast- and slow-twitch limb muscle phenotypes in cachectic mice through sirtuin-1 activation, attenuation of atrophy signaling pathways, and proteolysis in cancer cachectic mice. These findings have future therapeutic implications as these natural compounds, separately or in combination, may be used in clinical settings of muscle mass loss and dysfunction including cancer cachexia.     

Inhibition of phospholipase D1 induces immunogenic cell death and potentiates cancer immunotherapy in colorectal cancer

Phospholipase D (PLD) is a potential therapeutic target against cancer. However, the contribution of PLD inhibition to the antitumor response remains unknown. We developed a potent and selective PLD1 inhibitor based on computer-aided drug design. The inhibitor enhanced apoptosis in colorectal cancer (CRC) cells but not in normal colonic cells, and in vitro cardiotoxicity was not observed. The inhibitor downregulated the Wnt/β-catenin signaling pathway and reduced the migration, invasion, and self-renewal capacity of CRC cells. In cancer, therapeutic engagement of immunogenic cell death (ICD) leads to more effective responses by eliciting the antitumor immunity of T cells. The CRC cells treated with the inhibitor showed hallmarks of ICD, including downregulation of “do not eat-me” signals (CD24, CD47, programmed cell death ligand 1 [PD-L1]), upregulation of “eat-me” signal (calreticulin), release of high-mobility group Box 1, and ATP. PLD1 inhibition subsequently enhanced the phagocytosis of cancer cells by macrophages through the surface expression of costimulatory molecules; as a result, the cancer cells were more susceptible to cytotoxic T-cell-mediated killing. Moreover, PLD1 inhibition attenuated colitis-associated CRC and orthotopically injected tumors, probably by controlling multiple pathways, including Wnt signaling, phagocytosis checkpoints, and immune signaling. Furthermore, combination therapy with a PLD1 inhibitor and an anti-PD-L1 antibody further enhanced tumor regression via immune activation in the tumor environment. Collectively, in this study, PLD1 was identified as a critical regulator of the tumor microenvironment in colorectal cancer, suggesting the potential of PLD1 inhibitors for cancer immunotherapy based on ICD and immune activation. PLD1 inhibitors may act as promising immune modulators in antitumor treatment via ICD.Subject terms: Colon cancer, Cancer microenvironment     

Some Natural Photosensitizers and Their Medicinal Properties for Use in Photodynamic Therapy

Despite significant advances in early diagnosis and treatment, cancer is one of the leading causes of death. Photodynamic therapy (PDT) is a therapy for the treatment of many diseases, including cancer. This therapy uses a combination of a photosensitizer (PS), light irradiation of appropriate length and molecular oxygen. The photodynamic effect kills cancer cells through apoptosis, necrosis, or autophagy of tumor cells. PDT is a promising approach for eliminating various cancers but is not yet as widely applied in therapy as conventional chemotherapy. Currently, natural compounds with photosensitizing properties are being discovered and identified. A reduced toxicity to healthy tissues and a lower incidence of side effects inspires scientists to seek natural PS for PDT. In this review, several groups of compounds with photoactive properties are presented. The use of natural products has been shown to be a fruitful approach in the discovery of novel pharmaceuticals. This review focused on the anticancer activity of furanocoumarins, polyacetylenes, thiophenes, tolyporphins, curcumins, alkaloid and anthraquinones in relation to the light-absorbing properties. Attention will be paid to their phototoxic and anti-cancer effects on various types of cancer.     

Senescent tumor cells: an overlooked adversary in the battle against cancer

Senescent cells in cancer tissue, including senescent fibroblasts and macrophages, have been reported to increase the malignant potency of cancer cells by secreting senescence-associated secretory phenotype (SASP). Otherwise, Senescence of tumor cells has been believed to inhibit tumor growth by halting the massive proliferation and increasing the chances of immune clearance. In particular, senescent tumor cells (STCs) have been thought that they rarely exist in carcinomas because oncogene-induced senescence needs to be overcome for protumorigenic cells to become malignant. However, recent studies have revealed that a considerable number of STCs are present in cancer tissue, even in metastatic sites. In fact, STCs are widely involved in cancer progression by leading to collective invasion and building a cytokine barrier to protect nonsenescent tumor cells from immune attack. Furthermore, therapy-induced STCs can induce tumor progression and recurrence by increasing stemness. However, obscure causative factors and their heterogeneity in various cancers make it difficult to establish the physiological role of STCs. Here, we summarize and review the current knowledge of the pathophysiology and role of STCs. We also outline the current status of therapeutic strategies for directly removing STCs or modulating the SASPs to maximize the positive functions of STCs while suppressing the negative functions.Subject terms: Cancer microenvironment, Cancer immunotherapy     

Activation of Stimulation of Interferon Genes (STING) Signal and Cancer Immunotherapy

Stimulator of interferon gene (STING), an intracellular receptor in the endoplasmic reticulum, could induce the production of cytokines such as type I interferon (IFN) by activating the cGAS-STING signal pathway. In recent years, activation of STING has shown great potential to enhance anti-tumor immunity and reshape the tumor microenvironment, which is expected to be used in tumor immunotherapy. A number of STING agonists have demonstrated promising biological activity and showed excellent synergistic anti-tumor effects in combination with other cancer therapies in preclinical studies and some clinical trials. The combination of STING agonists and ICI also showed a potent effect in improving anti-tumor immunity. In this review, we introduce the cGAS-STING signaling pathway and its effect in tumor immunity and discuss the recent strategies of activation of the STING signaling pathway and its research progress in tumor immunotherapy.     

Small but mighty: the causes and consequences of micronucleus rupture

Micronuclei are small DNA-containing nuclear structures that are spatially isolated from the main nucleus. They are frequently found in pathologies, including cancer. It was recently shown that these nuclear structures are not only biomarkers of disease but also play an active role in tumor biology. Many consequences of micronucleus formation on tumor biology are dependent on the frequent and irreversible rupture of their nuclear envelopes, which results in the exposure of their DNA contents to the cytoplasm. In this review, we discuss models of defective nuclear envelope deposition on missegregated chromosomes that lead to nuclear envelope rupture. Furthermore, we expound upon the various downstream consequences of micronucleus nuclear envelope rupture on cells. These consequences include a massive DNA rearrangement phenomenon called chromothripsis and activation of the cGAS-STING innate immune signaling pathway, which can be a double-edged sword with tumorigenesis and tumor prevention functions. Although micronuclei are small structures, the impact they have on cells and their microenvironment is quite large.Subject terms: Cell biology, Cancer     

Pharmacological Properties of 4′, 5, 7-Trihydroxyflavone (Apigenin) and Its Impact on Cell Signaling Pathways

Plant bioactive compounds, particularly apigenin, have therapeutic potential and functional activities that aid in the prevention of infectious diseases in many mammalian bodies and promote tumor growth inhibition. Apigenin is a flavonoid with low toxicities and numerous bioactive properties due to which it has been considered as a traditional medicine for decades. Apigenin shows synergistic effects in combined treatment with sorafenib in the HepG2 human cell line (HCC) in less time and statistically reduces the viability of tumor cells, migration, gene expression and apoptosis. The combination of anti-cancerous drugs with apigenin has shown health promoting potential against various cancers. It can prevent cell mobility, maintain the cell cycle and stimulate the immune system. Apigenin also suppresses mTOR activity and raises the UVB-induced phagocytosis and reduces the cancerous cell proliferation and growth. It also has a high safety threshold, and active (anti-cancer) doses can be gained by consuming a vegetable and apigenin rich diet. Apigenin also boosted autophagosome formation, decreased cell proliferation and activated autophagy by preventing the activity of the PI3K pathway, specifically in HepG2 cells. This paper provides an updated overview of apigenin’s beneficial anti-inflammatory, antibacterial, antiviral, and anticancer effects, making it a step in the right direction for therapeutics. This study also critically analyzed the effect of apigenin on cancer cell signaling pathways including the PI3K/AKT/MTOR, JAK/STAT, NF-κB and ERK/MAPK pathways.     

The Potential Role of Apigenin in Cancer Prevention and Treatment

Cancer is the leading cause of death worldwide. In spite of advances in the treatment of cancer, currently used treatment modules including chemotherapy, hormone therapy, radiation therapy and targeted therapy causes adverse effects and kills the normal cells. Therefore, the goal of more effective and less side effects-based cancer treatment approaches is still at the primary position of present research. Medicinal plants or their bioactive ingredients act as dynamic sources of drugs due to their having less side effects and also shows the role in reduction of resistance against cancer therapy. Apigenin is an edible plant-derived flavonoid that has received significant scientific consideration for its health-promoting potential through modulation of inflammation, oxidative stress and various other biological activities. Moreover, the anti-cancer potential of apigenin is confirmed through its ability to modulate various cell signalling pathways, including tumor suppressor genes, angiogenesis, apoptosis, cell cycle, inflammation, apoptosis, PI3K/AKT, NF-κB, MAPK/ERK and STAT3 pathways. The current review mainly emphases the potential role of apigenin in different types of cancer through the modulation of various cell signaling pathways. Further studies based on clinical trials are needed to explore the role of apigenin in cancer management and explain the possible potential mechanisms of action in this vista.     

Cytotoxic and Proapoptotic Effects of Resveratrol in In Vitro Studies on Selected Types of Gastrointestinal Cancers

Cancer diseases are currently one of the greatest health challenges in clinical medicine worldwide. Classic methods of treatment often lead to numerous side effects, including the development of multidrug resistance. For this reason, increasing hope is being placed on compounds of natural origin, mainly due to their pleiotropic effect on different types of cells, protective effect on normal cells and toxic effect on cancerous ones. The most studied group are the polyphenolic compounds, which include resveratrol. The effectiveness of polyphenols in the treatment and prevention of many diseases, including cancer of various origins, has become the basis of many scientific studies. The anticancer effect of resveratrol has been demonstrated at all stages of the carcinogenesis process. Additionally, whether administered by itself or in combination with cytostatics, it may play a significant role in the process of reversing multidrug resistance. A review of the effects of resveratrol in in vitro conditions proves that it has a stronger or weaker antiproliferative and proapoptotic effect on the cells of certain neoplasms of the gastrointestinal tract. Despite the differences in the effect of this compound on different types of cancer, a similar tendency can be observed especially regarding the correlation between the concentration of the compound and the incubation time on the one hand and the antitumour effect on the other hand. The information included in this review may prove helpful in planning in vivo and clinical studies in the future.