Current Pharmaceutical Design - Volume 26, Issue 4, 2020

Melanoma is the deadliest type of skin cancers, accounting for more than 80% of skin cancer mortality. Although melanoma was known very early in the history of medicine, treatment for this disease had remained largely the same until very recently. Previous treatment options, including removal surgery and systemic chemotherapy, offered little benefit in extending the survival of melanoma patients. However, the last decade has seen breakthroughs in melanoma treatment, which all emerged following new insight into the oncogenic signaling of melanoma. This paper reviewed the evolution of drug targets for melanoma treatment based on the emergence of novel findings in the molecular signaling of melanoma. One of the findings that are most influential in melanoma treatment is that more than 50% of melanoma tumors contain BRAF mutations. This is fundamental for the development of BRAF inhibitors, which is the first group of drugs that significantly improves the overall survival of melanoma patients compared to the traditional chemotherapeutic dacarbazine. More recently, findings of the role of immune checkpoint molecules such as CTLA-4 and PD1/PD-L1 in melanoma biology have led to the development of a new therapeutic category: immune checkpoint inhibitors, which, for the first time in the history of cancer treatment, produced a durable response in a subset of melanoma patients. However, as this paper discussed next, there is still an unmet need for melanoma treatment. A significant population of patients did not respond to either BRAF inhibitors or immune checkpoint inhibitors. Of those patients who gained an initial response from those therapies, a remarkable percentage would develop drug resistance even when MEK inhibitors were added to the treatment. Finally, this paper discusses some possible targets for melanoma treatment.

Hepatocellular carcinoma (HCC) accounts for about 80-90% of all liver cancers and is found to be the third most common cause of cancer mortality in the Asia-Pacific region. Risk factors include hepatitis B and C virus, cirrhosis, aflatoxin-contaminated food, alcohol, and diabetes. Surgically removing the tumor tissue seems effective but a high chance of recurrence has led to an urgent need to develop novel molecules for the treatment of HCC. Clinical management with sorafenib is found to be effective but it is only able to prolong survival for a few months. Various side effects like gastrointestinal and abdominal pain, hypertension, and hemorrhage are also associated with sorafenib, which calls for the unmet need of effective therapies against HCC. Similarly, the genetic mechanisms behind the occurrence of HCC are still unknown and need to be expounded further for developing newer candidates. Since unearthing the concept of these variants, transcriptomics has revealed the role of noncoding RNAs (ncRNAs) in many cellular, physiological and pathobiological processes. They are also found to be widely associated and abundantly expressed in a variety of cancer. Aberrant expression and mutations are closely related to tumorigenesis and metastasis and hence are classified as novel biomarkers and therapeutic targets for the treatment of cancer, including HCC. Herein, this review summarises the relationship between ncRNAs and hepatocellular carcinoma.

Cancer cell biology takes advantage of identifying diverse cellular signaling pathways that are disrupted in cancer. Signaling pathways are an important means of communication from the exterior of cell to intracellular mediators, as well as intracellular interactions that govern diverse cellular processes. Oncogenic mutations or abnormal expression of signaling components disrupt the regulatory networks that govern cell function, thus enabling tumor cells to undergo dysregulated mitogenesis, to resist apoptosis, and to promote invasion to neighboring tissues. Unraveling of dysregulated signaling pathways may advance the understanding of tumor pathophysiology and lead to the improvement of targeted tumor therapy. In this review article, different signaling pathways and how their dysregulation contributes to the development of tumors have been discussed.

Interferons are secreted cytokines with potent antiviral, antitumor and immunomodulatory functions. As the first line of defense against viruses, this pathway restricts virus infection and spread. On the contrary, viruses have evolved ingenious strategies to evade host immune responses including the interferon pathway. Multiple families of viruses, in particular, DNA viruses, encode microRNA (miR) that are small, non-protein coding, regulatory RNAs. Virus-derived miRNAs (v-miR) function by targeting host and virus-encoded transcripts and are critical in shaping host-pathogen interaction. The role of v-miRs in viral pathogenesis is emerging as demonstrated by their function in subverting host defense mechanisms and regulating fundamental biological processes such as cell survival, proliferation, modulation of viral life-cycle phase. In this review, we will discuss the role of v-miRs in the suppression of host genes involved in the viral nucleic acid detection, JAK-STAT pathway, and cytokine-mediated antiviral gene activation to favor viral replication and persistence. This information has yielded new insights into our understanding of how v-miRs promote viral evasion of host immunity and likely provide novel antiviral therapeutic targets.

Background: The resistance of cancer cells to different therapies is one of the major stumbling blocks for successful cancer treatment. Various natural and pharmaceuticals drugs are unable to control drug-resistance cancer cell's growth. Also, chemotherapy and radiotherapy have several side effects and cannot apply to the patient in excess. In this context, chemosensitization to the therapy-resistant cells by non-toxic phytochemicals could be an excellent alternative to combat therapy-resistant cancers. Objective: To review the currently available literature on chemosensitization of therapy resistance cancers by Lupeol for clinically approved drugs through targeting different cell signaling pathways. Methods: We reviewed relevant published articles in PubMed and other search engines from 1999 to 2019 to write this manuscript. The key words used for the search were “Lupeol and Cancer”, “Lupeol and Chemosensitization”, “Lupeol and Cell Signaling Pathways”, “Cancer Stem Cells and Lupeol” etc. The published results on the chemosensitization of Lupeol were compared and discussed. Results: Lupeol chemosensitizes drug-resistant cancer cells for clinically approved drugs. Lupeol alone or in combination with approved drugs inhibits inflammation in different cancer cells through modulation of expression of IL-6, TNF-α, and IFN-γ. Lupeol, through altering the expression levels of BCL-2, BAX, Survivin, FAS, Caspases, and PI3K-AKT-mTOR signaling pathway, significantly induce cell deaths among therapy-resistant cells. Lupeol also modulates the molecules involved in cell cycle regulation such as Cyclins, CDKs, P53, P21, and PCNA in different cancer types. Conclusion: Lupeol chemosensitizes the therapy-resistant cancer cells for the treatment of various clinically approved drugs via modulating different signaling pathways responsible for chemoresistance cancer. Thus, Lupeol might be used as an adjuvant molecule along with clinically approved drugs to reduce the toxicity and increase the effectiveness.

Substance-use disorder represents a frequently hidden non-communicable chronic disease. Patients with intravenous drug addiction are at high risk of direct exposure to a variety of viral infections and are considered to be the largest subpopulation infected with the hepatitis C virus. Ribavirin is a synthetic nucleoside analog that has been used as an integral component of hepatitis C therapy. However, ribavirin medication is quite often associated with pronounced psychiatric adverse effects. It is not well understood to what extent ribavirin per se contributes to changes in drug-related neurobehavioral disturbances, especially in the case of psychostimulant drugs, such as amphetamine. It is now well-known that repeated amphetamine usage produces psychosis in humans and behavioral sensitization in animals. On the other hand, ribavirin has an affinity for adenosine A1 receptors that antagonistically modulate the activity of dopamine D1 receptors, which play a critical role in the development of behavioral sensitization. This review will focus on the current knowledge of neurochemical/ neurobiological changes that exist in the psychostimulant drug-addicted brain itself and the antipsychotic-like efficiency of adenosine agonists. Particular attention will be paid to the potential side effects of ribavirin therapy, and the opportunities and challenges related to its application in already existing psychostimulant-use disorder.

Mitochondria are the crucial regulators for the major source of ATP for different cellular events. Due to damage episodes, mitochondria have been established for a plethora ofalarming signals of stress that lead to cellular deterioration, thereby causing programmed cell death. Defects in mitochondria play a key role in arbitrating pathophysiological machinery with recent evince delineating a constructive role in mitophagy mediated mitochondrial injury. Mitophagy has been known for the eradication of damaged mitochondria via the autophagy process. Mitophagy has been investigated as an evolutionarily conserved mechanism for mitochondrial quality control and homeostasis. Impaired mitophagy has been critically linked with the pathogenesis of inflammatory diseases. Nevertheless, the exact mechanism is not quite revealed, and it is still debatable. The purpose of this review was to investigate the possible role of mitophagy and its associated mechanism in inflammation-mediated diseases at both the cellular and molecular levels.

The hyperactive RAS and inflammation are closely associated. The angiotensin-II/AT1R axis of the RAS has been explored extensively for its role in inflammation and a plethora of pathological conditions. Understanding the role of AT2R in inflammation is an emerging area of research. The AT2R is expressed on a variety of immune and non-immune cells, which upon activation triggers the release of a host of cytokines and has multiple effects that coalesce to anti-inflammation and prevents maladaptive repair. The anti-inflammatory outcomes of AT2R activation are linked to its well-established signaling pathways involving formation of nitric oxide and activation of phosphatases. Collectively, these effects promote cell survival and tissue function. The consideration of AT2R as a therapeutic target requires further investigations.

G-protein-coupled receptors (GPCRs) are membrane-bound proteins, which are responsible for the detection of extracellular stimuli and the origination of intracellular responses. Both glucagon and glucagon-like peptide-1 (GLP-1) receptors belong to G protein-coupled receptor (GPCR) superfamily. Along with insulin, glucagon and GLP-1 are critical hormones for maintaining normal serum glucose within the human body. Glucagon generally plays its role in the liver through cyclic adenosine monophosphate (cAMP), where it compensates for the action of insulin. GLP-1 is secreted by the L-cells of the small intestine to stimulate insulin secretion and inhibit glucagon action. Despite extensive research efforts and the multiple approaches adopted, the glycemic control in the case of type-2 diabetes mellitus remains a major challenge. Therefore, a deep understanding of the structure-function relationship of these receptors will have great implications for future therapies in order to maintain a normal glucose level for an extended period of time. The antagonists of glucagon receptors that can effectively block the hepatic glucose production, as a result of glucagon action, are highly desirable for the tuning of the hyperglycemic state in type 2 diabetes mellitus. In the same manner, GLP-1R agonists act as important treatment modalities, thanks to their multiple anti-diabetic actions to attain normal glucose levels. In this review article, the structural diversity of glucagon and GLP-1 receptors along with their signaling pathways, site-directed mutations and significance in drug discovery against type-2 diabetes are illustrated. Moreover, the promising non-peptide antagonists of glucagon receptor and agonists of GLP-1 receptor, for the management of diabetes are presented with elaboration on the structure-activity relationship (SAR).

With respect to the total cure failure of current drugs used in the treatment of neurodegenerative diseases, alternative strategies are followed. Particularly, neuroprotection approaches are questioned. Metal chelation, antioxidant towards oxidative stress, modulation of the amyloidogenic pathway, MAO-B inhibition, and NMDA receptor antagonism is more or less typical examples. Some of the representative drug candidates with promising neuroprotective features are assessed in clinical trials. Although initial attempts were found hopeful, none of the candidates have been found successful in each required clinical trials, particularly depending on the failures in terms of cognitive enhancement and slowing the progressive characteristics of neurodegenerative diseases. Today, neuroprotection is evaluated using multi-target ligand-based drug design studies. Within this study, the clinical outcomes of these studies, the rationale behind the design of the molecules are reviewed concomitant to the representative drug candidates of each group.