Anticancer Weapons Research Articles

Vitamin A - potential anticancer weapon

Introduction: Vitamin A, one of the most popular vitamins that people usually associate with eye health or beautiful skin, also has many other functions and uses. Recently many scientists conducted studies to determine if vitamin A could be a new weapon against cancers. Aim of the study: The aim of the study was to discuss recent findings regarding the impact of Vitamin A and other retinoids on potential applications in anticancer therapy. Materials and methods: This review of studies is based on scientific articles available in PubMed and Google Scholar databases. The names of the cancers were juxtaposed with term "Vitamin A" and with term "Retinoids" to gather data regarding the effect of retinoids on cancer treatment and prevention. Results: After analyzing the gathered publications, it is possible to conclude that retinoids can have a positive impact on cancer treatment. Some of them can induce apoptosis of cancer cells and others can reduce their proliferation. Moreover, retinoids can also play an important role in preventing cancers, such as ovarian, breast, cervical, or skin cancer. The role of retinoids in the prevention of prostate cancer remains unclear due to conflicting research results. Conclusion: The studies have shown promising results which indicate a need for further research into anticancer mechanisms of retinoids. Specifically, more research is needed to explore the positive impact of retinoid use in treating cancer diseases. The significant potential of retinoids may make it possible to include them in clinical practice and develop an effective therapeutic strategy for cancer treatment based on them.

FGFR1 promotes tumor immune evasion via YAP-mediated PD-L1 expression upregulation in lung squamous cell carcinoma

BackgroundVariations in FGFR1 are common driver mutations of LSQCC. And immune checkpoint inhibitors targeting PD-1 and PD-L1 are powerful anticancer weapons. Activation of FGFR1 leads to tumorigenesis through multiple downstream molecules, including YAP, but whether and how FGFR1 regulates tumor immune evasion remain largely unclear. MethodsLSQCC cells were modified to increase or decrease the expression of FGFR1, YAP and PD-L1, as assessed by molecular assays. After FGFR1 knockdown, cancer cells were assessed after cocultured with Jurkat T cells in vitro, and the tumor microenvironment were analyzed in C57BL/6 mice. The effect of the combination of FGFR1 knockdown and PD-1 blockade was also explored. ResultsIn human LSQCC, activation of FGFR1 was positively correlated with transcription of PD-L1. In H520 and HCC95 cells, FGFR1 upregulated PD-L1 expression via YAP, and YAP initiated the transcription of PD-L1 after binding to its promoter region. FGFR1 knockdown decreased tumor growth, reduced immune escape and induced reactivation of CD8+ T cells. The combination of FGFR1 knockdown and PD-1 blockade synergistically exerted antitumor effects. ConclusionsThe FGFR1/YAP/PD-L1 regulatory axis mediates tumor-associated immune suppression in lung squamous cell carcinoma, and FGFR1 knockdown reactivates T cells in the tumor microenvironment. Synergistic inhibition of both FGFR1 and PD-1/PD-L1 pathways may be a possible treatment for lung cancer patients.

Biomimetic metal–organic frameworks navigated biological bombs for efficient lung cancer therapy

The rising risk of lung cancer has become a primary global concern with high mortality and mobility. Presently, clinically used anticancer drugs show limited efficacy and significant side effects. A new generation of anticancer weapons is in great demand for lung cancer therapy. Herein, we have developed a novel style of biomimetic zeolitic imidazolate framework-8 (ZIF-8) based on the merits of cell membranes derived from human bone marrow mesenchymal stem cells (hBMSCs), which can navigate biological bombs herpes simplex virus type I thymidine kinase-encoded plasmids (pHSVtk) and ganciclovir (GCV) to treat lung cancer. The biological bomb-loaded structure can kill transfected lung cancer cells and neighboring lung cancer cells through the “bystander effect,” which induces efficient suppression of lung cancer both in vitro and in vivo. The biomimetic nanoparticles show an enhanced circulation lifetime and drug accumulation in the tumor tissues and significantly inhibit the tumors. We have developed a straightforward approach to deliver biological bombs with biomimetic metal–organic frameworks for efficient lung cancer therapy. To the best of our knowledge, this is the first report of such a strategy for lung cancer therapy.

The Green Anti-Cancer Weapon. The Role of Natural Compounds in Bladder Cancer Treatment.

Bladder cancer (BC) is the second most common genitourinary cancer. In 2018, 550,000 people in the world were diagnosed with BC, and the number of new cases continues to rise. BC is also characterized by high recurrence risk, despite therapies. Although in the last few years, the range of BC therapy has considerably widened, it is associated with severe side effects and the development of drug resistance, which is hampering treatment success. Thus, patients are increasingly choosing products of natural origin as an alternative or complementary therapeutic options. Therefore, in this article, we aim to elucidate, using the available literature, the role of natural substances such as curcumin, sulforaphane, resveratrol, quercetin, 6-gingerol, delphinidin, epigallocatechin-3-gallate and gossypol in the BC treatment. Numerous clinical and preclinical studies point to their role in the modulation of the signaling pathways, such as cell proliferation, cell survival, apoptosis and cell death.

Cellular senescence: from anti-cancer weapon to anti-aging target.

Cellular senescence (CS) is a state of stable cell cycle arrest characterized by the production and secretion of inflammatory molecules. Early studies described oncogene-induced senescence (OIS) as a barrier to tumorigenesis, such that the therapeutic induction of CS might represent a rational anti-cancer strategy. Indeed, the validity of this approach has been borne out by the development and approval of the cyclin-dependent kinase (CDK) inhibitor palbociclib for the treatment of breast cancer. Apart from tumors, senescent cells have also been shown to accumulate during natural mammalian aging, where they produce detrimental effects on the physiology of surrounding tissues. Thus, pharmacological senescent cell depletion has been proposed as an approach to delay age-related functional decline; this has been formally demonstrated in animal models. In this review article, we describe the current mechanistic understanding of cellular senescence at the molecular level and how it informs the development of new therapeutic strategies to combat cancer and aging.

Graphene oxide arms oncolytic measles virus for improved effectiveness of cancer therapy

BackgroundReplication-competent oncolytic viruses (OVs) have been proven to be a potent anticancer weapon for clinical therapy. The preexisting neutralizing antibody in patients is a big challenge for oncolytic efficacy of OVs. Graphene oxide sheets (GOS) possess excellent biological compatibility and are easy to decorate for targeted delivery.MethodsWe generated PEI-GOS-PEG-FA (Polyethyleneimine-Graphene oxide sheets-Polyethylene glycol-Folic acid). After intravenous injection, the distribution of PEI-GOS-PEG-FA in tumor-bearing mice was visualized by the IVIS Lumina XR system. Then, the oncolytic measles virus (MV-Edm) was coated with PEI-GOS-PEG-FA to form a viral-GOS complex (GOS/MV-Edm). The oncolytic effects of GOS/MV-Edm were investigated both in vitro and in vivo.ResultsGOS/MV-Edm exhibited higher infectivity and enhanced oncolysis. In tumor-bearing mice, GOS/MV-Edm had significantly elevated viral replication within the tumor mass, and achieved an improved antitumor effect. Then, we confirmed that GOS/MV-Edm entered cancer cells via the folate receptor instead of CD46, a natural cognate receptor of MV-Edm. GOS/MV-Edm remained the infectivity in murine cells that lack CD46. Finally, we found that GOS/MV-Edm was effectively protected from neutralization in the presence of antiserum both in vitro and in vivo. In passively antiserum immunized tumor-bearing mice, the survival was remarkably improved with intravenous injection of GOS/MV-Edm.ConclusionOur findings demonstrate that GOS/MV-Edm displays significantly elevated viral replication within the tumor mass, leading to an improved antitumor effect in solid tumor mouse model. Our study provided a novel strategy to arm OVs for more efficient cancer therapy. That may become a promising therapeutic strategy for cancer patients.

MicroRNA-124: An emerging therapeutic target in cancer.

MicroRNAs (miRNAs) are noncoding single‐stranded RNAs, approximately 20‐24 nucleotides in length, known as powerful posttranscriptional regulators. miRNAs play important regulatory roles in cellular processes by changing messenger RNA expression and are widely involved in human diseases, including tumors. It has been reported in the literature that miRNAs have a precise role in cell proliferation, programmed cell death, differentiation, and expression of coding genes. MicroRNA‐124 (miR‐124) has reduced exparession in various human neoplasms and is believed to be related to the occurrence, development, and prognosis of malignant tumors. In our review, we focus on the specific molecular functions of miR‐124 and the downstream gene targets in major cancers, which provide preclinical evidence for the treatment of human cancer. Although some obstacles exist, miR‐124 is still attracting intensive research focus as a promising and effective anticancer weapon.

3 Questions on...A Re-Engineered Cold Virus May Be an Anti-Cancer Weapon

3 Questions on...A Re-Engineered Cold Virus May Be an Anti-Cancer Weapon

Viruses as anticancer weapons

Viruses as anticancer weapons

How to develop viruses into anticancer weapons.

Viruses have shaped human history through devastating infections. In addition, virus infection may be responsible for up to 15% of cancer deaths [1]. Nevertheless, certain viruses can be our “friends.” At the end of the 18th century, Edward Jenner used cowpox to protect humans against infection with a lethal pathogen, smallpox. Based on the effectiveness of this “vaccination” process, in the 1960s, the World Health Organization mounted a global vaccination campaign that resulted in the eradication of smallpox [2]. In the mid-20th century, the principle of virus attenuation through adaptation to unnatural hosts was extended to cultured cells: cells from different species were used to select viruses with multiple mutations, reducing replication speed and allowing the immune system to control viral infection. Based on such a “live-attenuated” vaccine, global eradication of another viral disease, rinderpest, was recently achieved [3]. Other global vaccination campaigns, including those against polio and measles, are progressing. In addition, subunit vaccines are proving to be effective against virus-induced cancers, preventing hepatitis B virus–induced hepatocellular carcinoma and human papilloma virus–induced cervical cancer [2, 4]. A new frontier is to develop viruses into anticancer weapons. Many cancers remain incurable despite recent advances in radio-, chemo-, and immunotherapy. Based on their preferential replication in tumor cells, viruses from nine families have progressed to clinical trials of oncolysis: DNA viruses include Adenoviridae, Herpesviridae, Parvoviridae, and Poxviridae and RNA viruses Paramyxoviridae, Picornaviridae, Reoviridae, Retroviridae, and Rhabdoviridae [5, 6]. Recently, a genetically modified herpes simplex virus 1–based oncolytic vector, named talimogene laherparepvec (T-VEC), was approved as cancer therapeutic in the United States and Europe [7]. What are the mechanisms supporting cancer therapy with viruses, and how can oncolytic virotherapy be improved?

Combining temozolomide with other antitumor drugs and target-based agents in the treatment of brain metastases: an unending quest or chasing a chimera?

Introduction: Medical treatment of brain metastases (BM) is still a controversial issue in cancer therapy being mainly limited by the existence of the BBB. Temozolomide (TMZ) can cross BBB and several clinical trials have been performed attempting to demonstrate the activity of TMZ in combination with whole brain radiotherapy (WBRT) in the treatment of BM.Areas covered: This review summarizes TMZ–WBRT combination trials highlighting the confounding factors that limit the interpretation of the achieved results and describes the main clinical trials using TMZ in combination with other cytotoxic or biological agents. The main limitations of these trials are: i) patient selection for heterogenous primitive neoplasms and for heterogeneous neuro-functional score; ii) poor penetration across BBB of the other drugs; iii) cumulative toxicity and iv) poor control of extracranial tumor sites.Expert opinion: Biotechnological, biological and biochemical advances in the management of BM could allow in short time the definition of new schedules based on the rational use of new anticancer weapons. The latter could be cytotoxic agents encapsulated in nanotechnological tools able to cross BBB, lipophilic small kinase inhibitors (lapatinib, sunitinib), mTOR inhibitors and PARP inhibitors combined with old drugs such as TMZ.

A new molecular targeted therapeutic approach for renal cell carcinoma with a p16 functional peptide using a novel transporter system

Molecular targeting agents have become formidable anticancer weapons showing much promise against refractory tumors and functional peptides and are among the more desirable of these nanobio-tools. Intracellular delivery of multiple functional peptides forms the basis for a potent, non-invasive mode of delivery, providing distinctive therapeutic advantages. We examine the growth suppression efficiency of human renal cell carcinoma (RCC) by single-peptide targeting. We simultaneously introduced p16INK4a tumor suppressor peptides by Wr-T-mediated peptide delivery. Wr-T-mediated transport of p16INK4a functional peptide into 10 RCC lines, lacking expression of the p16INK4a molecule, reversed the specific loss of p16 function, thereby drastically inhibiting tumor growth in all but 3 lines by >95% within the first 96h. Invivo analysis using SK-RC-7 RCC xenografts in nude mice demonstrated tumor growth inhibition by the p16INK4a peptide alone, however, inoculation of Wr-T and the p16INK4a functional peptide mixture, via the heart resulted in complete tumor regression. Thus, restoration of tumor suppressor function with Wr-T peptide delivery represents a powerful approach, with mechanistic implications for the development of efficacious molecular targeting therapeutics against intractable RCC.

Bacterial anticancer weapons: a promising tool to fight cancer

Pseudomonas aeruginosa is an opportunistic extracellular pathogen for debilitated or immuno-compromised patients, capable of forming biofilms on the epithelial surfaces of various tissues in such patients. The biofilm formation allows the pathogen to evade antibiotic therapy or immune attack, ensuring its long term residence and a niche in the body. Any subsequent attack by an internal or external invader such as cancers, viruses or parasites can threaten and cause the resident bacteria to lose their sanctuary. Consequently, P. aeruginosa appears to produce protein weapons, such as azurin, that has structural similarity to immunoglobulins and that can preferentially enter to cancer cells and bind many important intracellular or extracellular proteins, including signalling proteins, that are important for cancer growth. Such binding results in the interference of multiple pathways by which cancer cells grow, significantly inhibiting their growth both in vitro and in vivo in live mice. Azurin can also prevent precancerous lesion formation in normal mouse mammary cells, when such cells are exposed to a carcinogen such as 7,12- dimethyl-benz-antracene, thus demonstrating cancer preventive activity, resembling a vaccine. In addition to its anticancer activity, azurin interferes in the growth of viruses such as HIV/AIDS and parasites such as the malarial parasite Plasmodium falciparum or the toxoplasmosis- causing parasite Toxoplasma gondii. Not only azurin, but some of the peptides derived from azurin such as P28, comprising of 28 azurin amino acid residues 50 to 77, demonstrate entry specificity in cancer cells and significant cytotoxicity including inhibition of angiogenesis. P28 is currently undergoing phase I human clinical trials in the Unites States with early encouraging results. The ability of azurin to interfere in multiple pathways by which cancer cells grow or interfere in the growth of HIV/AIDS virus or malarial, taxoplasmosis parasites distinguishes it from rationally designed anticancer drugs of the pharmaceutical industry which inhibit a single or a limited number of validated targets in the growth progression pathways of the cancer cells. The cancer cells respond to such rationally designed drugs by changing or switching off the target, thereby rapidly becoming drug resistant. It remains to be seen if azurin will demonstrate efficacy in human patients suffering from multiple diverse diseases such as cancers, HIV/AIDS and malaria, and if effective, may exhibit much less susceptibility to resistance development by the disease agents.

Turning Tumor-Promoting Copper into an Anti-Cancer Weapon via High-Throughput Chemistry

Copper is an essential element for multiple biological processes. Its concentration is elevated to a very high level in cancer tissues for promoting cancer development through processes such as angiogenesis. Organic chelators of copper can passively reduce cellular copper and serve the role as inhibitors of angiogenesis. However, they can also actively attack cellular targets such as proteasome, which plays a critical role in cancer development and survival. The discovery of such molecules initially relied on a step by step synthesis followed by biological assays. Today high-throughput chemistry and high-throughput screening have significantly expedited the copper-binding molecules discovery to turn "cancer-promoting" copper into anti-cancer agents.

Potent synergy of dual antitumor peptides for growth suppression of human glioblastoma cell lines

Molecular targeting agents have become formidable anticancer weapons, which show much promise against the refractory tumors. Functional peptides are among the more desirable of these nanobio-tools. Intracellular delivery of multiple functional peptides forms a basis for potent, non-invasive mode of delivery, providing distinctive therapeutic advantages. Here, we examine growth suppression efficiency of human glioblastomas by dual-peptide targeting. We did simultaneous introduction of two tumor suppressor peptides (p14(ARF) and p16(INK4a) or p16(INK4a) and p21(CIP1) functional peptides) compared with single-peptide introduction using Wr-T-mediated peptide delivery. Wr-T-mediated transport of both p14(ARF) and p16(INK4a) functional peptides (p14-1C and p16-MIS, respectively) into human glioblastoma cell line, U87DeltaEGFR, reversed specific loss of p14 and p16 function, thereby drastically inhibiting tumor growth by >95% within the first 72 h, whereas the growth inhibition was approximately 40% by p14 or p16 single-peptide introduction. Additionally, the combination of p16 and p21(CIP1) (p21-S154A) peptides dramatically suppressed the growth of glioblastoma line Gli36DeltaEGFR, which carries a missense mutation in p53, by >97% after 120 h. Significantly, our murine brain tumor model for dual-peptide delivery showed a substantial average survival enhancement (P < 0.0001) for peptide-treated mice. Wr-T-mediated dual molecular targeting using antitumor peptides is highly effective against growth of aggressive glioblastoma cells in comparison with single molecule targeting. Thus, jointly restoring multiple tumor suppressor functions by Wr-T-peptide delivery represents a powerful approach, with mechanistic implications for development of efficacious molecular targeting therapeutics against intractable human malignancies.

Cellules dendritiques et gliomes : un espoir en immunothérapie ?

Immunotherapy has been explored for several decades to try to improve the prognosis of gliomas, but until recently no therapeutic benefit has been achieved. The discovery of dendritic cells, the most potent professional antigen presenting cells to initiate specific immune response, and the possibility of producing them ex vivo gave rise to new protocols of active immunotherapy. In oncology, promising experimental and clinical therapeutic results were obtained using these dendritic cells loaded with tumor antigen. Patients bearing gliomas have deficit antigen presentation making this approach rational. In several experimental glioma models, independent research teams have showed specific antitumor responses using these dendritic cells. Phase I/II clinical trials have demonstrated the feasibility and the tolerance of this immunotherapeutic approach. In neuro-oncology, the efficiency of such an approach remains to be established, similarly in oncology where positive phase III studies are missing. Nevertheless, dendritic cells comprise a complex network which is only partially understood and capable of generating either immunotolerance or immune response. Numerous parameters remain to be explored before any definitive conclusion about their utility as an anticancer weapon can be drawn. It seems however logical that immunotherapy with dendritic cells could prevent or delay tumor recurrence in patients with minor active disease. A review on glioma and dendritic cells is presented.

Good Cytokine: Bad Cytokine

The interplay between the immune system and cancer cells is a complicated one. On the one hand, inflammation associated with tumors is similar to that of protective immune responses and inhibition of responses like turnover of extracellular matrix and angiogenesis, so inhibition of these responses can suppress tumor growth. But immune responses such as the accumulation of tumor-infiltrating T cells are a potent defense mechanism against cancer cells. Can the balance of these effects be altered to enhance therapeutic strategies against cancer? Langowski et al. suggest that signaling by the cytokine interleukin 23 (IL-23) might provide an inroad to such a strategy. IL-23 has beneficial effects in promoting immune responses to bacterial infections. The authors found, however, that expression of IL-23 was increased in samples of human cancer tissues, and its role proved to be not nearly so helpful in fighting off the invading cancer cells. Instead, mice lacking the p19 subunit necessary for formation of the cytokine were resistant to chemical carcinogenesis. Loss of IL-23 was also associated with decreases in several inflammatory effects that contribute to tumor promotion. Furthermore, infiltration of cytotoxic CD8 + T cells--which form a front line of defense in the body's attack on tumor cells--was inhibited by IL-23 and enhanced in its absence. Transplanted tumors grew more poorly in mice that lacked functional IL-23 or its receptor. Thus, the authors conclude that IL-23 is not only ineffective at fighting tumors but actually promotes changes in the tumor environment that enhance or protect tumor growth. This, of course, suggests that therapies to limit IL-23 function may be appropriate new additions to the arsenal of anticancer weapons. J. L. Langowski, X. Zhang, L. Wu, J. D. Mattson, T. Chen, K. Smith, B. Basham, T. McClanahan, R. A. Kastelein, M. Oft, IL-23 promotes tumour incidence and growth. Nature 442 , 461-465 (2006). [PubMed]

Activation of cytotoxic T cells by solid tumours?

Tumour-specific cytotoxic T cells (CTLs) are among the best-defined biological anticancer weapons. Nevertheless, they often fail to control tumour growth in vivo. Many reasons for this have been evoked: tumours may actively inhibit CTLs, or may protect themselves from CTL recognition by various means. However, one does not necessarily need to postulate such active immune evasion mechanisms specifically acquired by tumour cells. In this review we argue that the failure of immune protection is due to the intrinsic inability of tumours to activate an effective immune response, and that many tumours are similar to normal tissues in this respect. It is striking to see that the majority of the so-called immune escape mechanisms are not specifically acquired by selected tumour cells, but are common mechanisms shared between solid tumours and normal, healthy tissues. Immune responses are poor because tumour antigens do not efficiently localize to lymph follicles in lymphoid tissues, and are not efficiently presented to CTLs in an immunogenic context. The fact that tumours do not induce CTLs but are often susceptible to lymphocyte-mediated cytotoxicity indicates that more intensified immunization protocols should result in improved clinical outcome.