Targeting apoptotic pathways for cancer therapy.

Apoptosis is a form of programmed cell death that is mediated by intrinsic and extrinsic pathways. Dysregulation of and resistance to cell death are hallmarks of cancer. For over three decades, the development of therapies to promote treatment of cancer by inducing various cell death modalities, including apoptosis, has been a main goal of clinical oncology. Apoptosis pathways also interact with other signaling mechanisms, such as the p53 signaling pathway and the integrated stress response (ISR) pathway. In addition to agents directly targeting the intrinsic and extrinsic pathway components, anticancer drugs that target the p53 and ISR signaling pathways are actively being developed. In this Review, we discuss selected and promising anticancer therapies in various stages of development, including drug targets, mechanisms, and resistance to related treatments, focusing especially on B cell lymphoma 2 (BCL-2) inhibitors, TRAIL analogues, DR5 antibodies, and strategies that target p53, mutant p53, and the ISR.

Therapeutic targeting of TRAIL death receptors.

The discovery of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) along with its potent and selective antitumor effects initiated a decades-long search for therapeutic strategies to target the TRAIL pathway. First-generation approaches were focused on the development of TRAIL receptor agonists (TRAs), including recombinant human TRAIL (rhTRAIL) and TRAIL receptor-targeted agonistic antibodies. While such TRAIL pathway-targeted therapies showed promise in preclinical data and clinical trials have been conducted, none have advanced to FDA approval. Subsequent second-generation approaches focused on improving upon the specific limitations of first-generation approaches by ameliorating the pharmacokinetic profiles and agonistic abilities of TRAs as well as through combinatorial approaches to circumvent resistance. In this review, we summarize the successes and shortcomings of first- and second-generation TRAIL pathway-based therapies, concluding with an overview of the discovery and clinical introduction of ONC201, a compound with a unique mechanism of action that represents a new generation of TRAIL pathway-based approaches. We discuss preclinical and clinical findings in different tumor types and provide a unique perspective on translational directions of the field.

Chitosan-Based Nanoparticles Against Viral Infections.

Viral infections, in addition to damaging host cells, can compromise the host immune system, leading to frequent relapse or long-term persistence. Viruses have the capacity to destroy the host cell while liberating their own RNA or DNA in order to replicate within additional host cells. The viral life cycle makes it challenging to develop anti-viral drugs. Nanotechnology-based approaches have been suggested to deal effectively with viral diseases, and overcome some limitations of anti-viral drugs. Nanotechnology has enabled scientists to overcome the challenges of solubility and toxicity of anti-viral drugs, and can enhance their selectivity towards viruses and virally infected cells, while preserving healthy host cells. Chitosan is a naturally occurring polymer that has been used to construct nanoparticles (NPs), which are biocompatible, biodegradable, less toxic, easy to prepare, and can function as effective drug delivery systems (DDSs). Furthermore, chitosan is Generally Recognized as Safe (GRAS) by the US Food and Drug Administration (U.S. FDA). Chitosan NPs have been used in drug delivery by the oral, ocular, pulmonary, nasal, mucosal, buccal, or vaginal routes. They have also been studied for gene delivery, vaccine delivery, and advanced cancer therapy. Multiple lines of evidence suggest that chitosan NPs could be used as new therapeutic tools against viral infections. In this review we summarize reports concerning the therapeutic potential of chitosan NPs against various viral infections.

Use of Salmonella Bacteria in Cancer Therapy: Direct, Drug Delivery and Combination Approaches.

Over the years, conventional cancer treatments, such as chemotherapy with only a limited specificity for tumors, have undergone significant improvement. Moreover, newer therapies such as immunotherapy have undergone a revolution to stimulate the innate as well as adaptive immune responses against the tumor. However, it has been found that tumors can be selectively colonized by certain bacteria, where they can proliferate, and exert direct oncolytic effects as well as stimulating the immune system. Bacterial-mediated cancer therapy (BMCT) is now one example of a hot topic in the antitumor field. Salmonella typhimurium is a Gram-negative species that generally causes self-limiting gastroenteritis in humans. This species has been designed and engineered in order to be used in cancer-targeted therapeutics. S. typhimurium can be used in combination with other treatments such as chemotherapy or radiotherapy for synergistic modification of the tumor microenvironment. Considerable benefits have been shown by using engineered attenuated strains for the diagnosis and treatment of tumors. Some of these treatment approaches have received FDA approval for early-phase clinical trials. This review summarizes the use of Salmonella bacteria for cancer therapy, which could pave the way towards routine clinical application. The benefits of this therapy include an automatic self-targeting ability, and the possibility of genetic manipulation to produce newly engineered attenuated strains. Nevertheless, Salmonella-mediated anticancer therapy has not yet been clinically established, and requires more research before its use in cancer treatment.

An Update on the Effects of Probiotics on Gastrointestinal Cancers.

Because of their increasing prevalence, gastrointestinal (GI) cancers are regarded as an important global health challenge. Microorganisms residing in the human GI tract, termed gut microbiota, encompass a large number of living organisms. The role of the gut in the regulation of the gut-mediated immune responses, metabolism, absorption of micro- and macro-nutrients and essential vitamins, and short-chain fatty acid production, and resistance to pathogens has been extensively investigated. In the past few decades, it has been shown that microbiota imbalance is associated with the susceptibility to various chronic disorders, such as obesity, irritable bowel syndrome, inflammatory bowel disease, asthma, rheumatoid arthritis, psychiatric disorders, and various types of cancer. Emerging evidence has shown that oral administration of various strains of probiotics can protect against cancer development. Furthermore, clinical investigations suggest that probiotic administration in cancer patients decreases the incidence of postoperative inflammation. The present review addresses the efficacy and underlying mechanisms of action of probiotics against GI cancers. The safety of the most commercial probiotic strains has been confirmed, and therefore these strains can be used as adjuvant or neo-adjuvant treatments for cancer prevention and improving the efficacy of therapeutic strategies. Nevertheless, well-designed clinical studies are still needed for a better understanding of the properties and mechanisms of action of probiotic strains in mitigating GI cancer development.

Gynecologic cancers and non-coding RNAs: Epigenetic regulators with emerging roles.

Gynecologic cancers involve the female genital organs, such as the vulva, vagina, cervix, endometrium, ovaries, and fallopian tubes. The occurrence and frequency of gynecologic cancer depends on personal lifestyle, history of exposure to viruses or carcinogens, genetics, body shape, and geographical habitat. For a long time, research into the molecular biology of cancer was broadly restricted to protein-coding genes. Recently it has been realized that non-coding RNAs (ncRNA), including long noncoding RNAs (LncRNAs), microRNAs, circular RNAs and piRNAs (PIWI-interacting RNAs), can all play a role in the regulation of cellular function within gynecological cancer. It is now known that ncRNAs are able to play dual roles, i.e. can exert both oncogenic or tumor suppressive functions in gynecological cancer. Moreover, several clinical trials are underway looking at the biomarker and therapeutic roles of ncRNAs. These efforts may provide a new horizon for the diagnosis and treatment of gynecological cancer. Herein, we summarize some of the ncRNAs that have been shown to be important in gynecological cancers.