Anti-Cancer Agents in Medicinal Chemistry (v.16, #1)

Meet Our Editorial Board Member: by Marco Folini (1-1).

Overview: by Michelle Prudhomme (2-2).

Preface: by Michelle Prudhomme (3-3).

Editorial (Thematic Issue: Antitarget Therapies: New Frontiers in the Treatment of Cancer) by Claudio Festuccia, Alessio Lodola, Giovanni Luca Gravina (4-6).

Therapeutic Use of MicroRNAs in Cancer by Alessandra Tessitore, Germana Cicciarelli, Valentina Mastroiaco, Filippo Del Vecchio, Daria Capece, Daniela Verzella, Mariafausta Fischietti, Davide Vecchiotti, Francesca Zazzeroni, Edoardo Alesse (7-19).
MicroRNAs are small non-coding RNAs which regulate gene expression and silence a wide set of target genes. Aberrant miRNA expression has been described in cancer cells and is at least in part responsible of cancer initiation, development and progression. Due to their role, miRNAs have emerged as therapeutic targets or molecules suitable at the therapeutic level as well as markers of the response to chemo/radio/targeted therapy. Restoration or repression of miRNAs expression and activity shows high potential in managing cancer, and many studies on pre-clinical models have demonstrated the feasibility and efficacy of miRNA-based therapy. However, despite the exciting potential, some limitations, due to the degree of delivery and biodistribution or to possible side effects, need to be taken into consideration and solved in order to accomplish transition to clinical application. In this review we report and discuss the role of miRNAs in cancer, focusing on their use as therapeutic agents and their involvement in modulating/affecting the response to chemo/radio/targeted therapy in some of the most frequent solid tumors.

Chemotherapy may still be an essential component to treat cancer in combination with new targeted therapies. But chemotherapy needs to get smarter in order to make those combination regimens more effective and also more tolerable, particularly for an aging population. We describe the first time the synthesis and pharmacological testing of a fusion molecule comprising of the alkylator bendamustine and the HDAC-inhibitor vorinostat. The drug was designed to allow for the exploitation of both mechanisms of action simultaneously with the goal to provide a molecule with superior efficacy over the single agents. The pharmacological testing confirms the full functional capacity of both moieties and encouraging pharmacological data raises the hope that the drug may turn out to be a great addition to the armentarium of anticancer agents.

Potential Molecular Targeted Therapeutics: Role of PI3-K/Akt/mTOR Inhibition in Cancer by Kevin M. Sokolowski, Steven Koprowski, Selvi Kunnimalaiyaan, Mariappan Balamurugan, T. Clark Gamblin, Muthusamy Kunnimalaiyaan (29-37).
Primary liver cancer is one of the most commonly occurring cancers worldwide. Hepatocellular carcinoma (HCC) represents the majority of primary liver cancer and is the 3rd most common cause of cancer-related deaths globally. Survival rates of patients with HCC are dependent upon early detection as concomitant liver dysfunction and advanced disease limits traditional therapeutic options such as resection or ablation. Unfortunately, at the time of diagnosis, most patients are not eligible for curative surgery and have a five-year relative survival rate less than 20%, leading to systemic therapy as the only option. Currently, sorafenib is the only approved systemic therapy; however, it has a limited survival advantage and low efficacy prompting alternative strategies. The inception of sorafenib for HCC systemic therapy and the understanding involved of cancer therapy have led to an enhanced focus of the PI3-k/Akt/mTOR pathway as a potential area of targeting including pan and isoform-specific PI3-K inhibitors, Akt blockade, and mTOR suppression. The multitude, expanding roles, and varying clinical trials of these inhibitors have led to an increase in knowledge and availability for current and future studies. In this review, we provide a review of the literature with the aim to focus on potential targets for HCC therapies as well as an in depth focus on Akt inhibition.

Targeting Cancer Stem Cells: Promises and Challenges by Jan Dominik Kuhlmann, Linda Hein, Ina Kurth, Pauline Wimberger, Anna Dubrovska (38-58).
Recent discoveries have provided the compelling evidence that stem cell populations within each individual tumor are key contributors of therapy failure regardless of whether these populations are transient or stable. Thus, it is becoming increasingly clear that efficient tumor treatment requires eradication of the entire CSC population. The potential role of CSCs in tumor initiation and relapse has motivated an investigation of the CSCspecific treatments. However, development of the therapeutic strategies targeting CSCs might be challenged by a high diversity and plasticity of CSC features. Moreover, taking in account that an origin of CSC remains controversial and accumulating experimental evidence suggests a possibility of tumor cell reprogramming, efficient anti-cancer treatment should eradicate both CSCs and tumor bulk as well as prevent tumor dedifferentiation. In this article we discuss new insights into the stem cell concept of tumor development, review the treatment strategies eradicating CSCs that have been evaluated in preclinical and clinical studies and summarize the strategies to identify new CSC-targeted therapy.

CXCR4 and Glioblastoma by Peter J. Richardson (59-74).
This article focuses on the possible application of antagonists of the G-protein coupled chemokine receptor, CXCR4, for the treatment of glioblastoma and summarises the evidence for CXCR4 antagonism being a viable therapeutic approach. Particular attention is paid to the role of this receptor in cancer stem cell biology, and the maintenance of CXCR4 expression by the glioblastoma key driver mutations. The expression of the CXCR4 receptor, and of its ligand stromal derived factor 1 (SDF-1, CXCL12), is maintained by intracellular pathways via positive feedback loops, and is associated with the epithelial mesenchymal transition (EMT) and the generation and self-renewal of cancer stem cells. SDF-1 and CXCR4 also play a role in the generation and maintenance of the perivascular stem cell niche which contains these cancer stem cells. The available data suggest that most, if not all, glioblastoma cancer stem cells rely on CXCR4 mediated signalling to maintain their phenotype. SDF-1 and CXCR4 are alsoinvolved in many other aspects of brain tumour biology including resistance to radio- and chemotherapy, the migration of cancer cells through the brain, the generation of the tumour blood supply and the recruitment of vascular progenitor cells. These properties suggest that a CXCR4 antagonist would help in the control of this disease.

Therapeutic Potential of Targeting PAK Signaling by William Senapedis, Marsha Crochiere, Erkan Baloglu, Yosef Landesman (75-88).
The therapeutic potential of targeting p21-Activated Kinases (PAK1 - 6) for the treatment of cancer has recently gained traction in the biotech industry. Many pharmaceutically-viable ATP competitive inhibitors have been through different stages of pre-clinical development with only a single compound evaluated in human trails (PF-3758309). The best studied functional roles of PAK proteins are control of cell adhesion and migration. PAK proteins are known downstream effectors of Ras signaling with PAK expression elevated in cancer (pancreatic, colon, breast, lung and other solid tumors). In addition altered PAK expression is a confirmed driver of this disease, especially in tumors harboring oncogenic Ras. However, there are very few examples of gain-of-function PAK mutations, as a majority of the cancer types have elevated PAK expression due to gene amplification or transcriptional modifications. There is a substantial number of known substrates affected by this aberrant PAK activity. One particular substrate, β-catenin, has garnered interest given its importance in both normal and cancer cell development. These data place PAK proteins between two major signaling pathways in cancer (Ras and β -catenin), making therapeutic targeting of PAKs an intriguing approach for the treatment of a broad array of oncological malignancies.

Nutrition, Nitrogen Requirements, Exercise and Chemotherapy-Induced Toxicity in Cancer Patients. A puzzle of Contrasting Truths? by Vincenzo Flati, Giovanni Corsetti, Evasio Pasini, Anna Rufo, Claudia Romano, Francesco Saverio Dioguardi (89-100).
Amino acids can modulate cell metabolism and control cell fate by regulating cell survival and cell death. The molecular mechanisms involved are mediated by the mTOR complexes mTORC1 and mTORC2 activity. These complexes are finely regulated and the continuous advancement of the knowledge on their composition and function is revealing that their balance may represent the condition that determines the cell fate. This is important for normal healthy cells but it is becoming clear, and it is even more important, that the balance of the mTORCs activity may also condition the cell fate of cancer cells. Here, we discuss the evidences supporting the amino acids supplementation as a cancer fighting weapon and a possible strategy to counteract the myocyte toxicity associated with chemotherapy, possibly by tipping the balance of mTORCs activity.

The Immune System in Cancer Prevention, Development and Therapy by Serge M. Candeias, Udo S. Gaipl (101-107).
The immune system plays a pivotal role in the maintenance of the integrity of an organism. Besides the protection against pathogens, it is strongly involved in cancer prevention, development and defense. This review focuses on how the immune system protects against infections and trauma and on its role in cancer development and disease. Focus is set on the interactions of the innate and adaptive immune system and tumors. The role of IFN-γ as a pleiotropic cytokine that plays a very important role at the interface of innate and adaptive immune systems in tumor development and induction of anti-tumor immune responses is outlined. Further, immune cells as prognostic and predictive markers of cancer will be discussed. Data are provided that even the brain as immune privileged organ is subjected to immune surveillance and consequently also brain tumors. Immune therapeutic approaches for glioblastoma multiforme, the most frequent and malignant brain tumor, based on vaccination with dendritic cells are outlined and application of hyperthermia in form of magnetic nanoparticles is discussed. We conclude that the immune system and developing tumors are intimately intertwined. Anti-tumor immune responses can be prominently boosted by multimodal therapies aiming on the one hand to induce immunogenic tumor cell death forms and on the other hand to actively counteract the immune suppressive microenvironment based on the tumor itself.

Exploring Cancer Therapeutics with Natural Products from African Medicinal Plants, Part II: Alkaloids, Terpenoids and Flavonoids by Justina N. Nwodo, Akachukwu Ibezim, Conrad V. Simoben, Fidele Ntie-Kang (108-127).
Cancer stands as second most common cause of disease-related deaths in humans. Resistance of cancer to chemotherapy remains challenging to both scientists and physicians. Medicinal plants are known to contribute significantly to a large population of Africa, which is to a very large extent linked to folkloric claims which is part of their livelihood. In this review paper, the potential of naturally occurring anti-cancer agents from African flora has been explored, with suggested modes of action, where such data is available. Literature search revealed plant-derived compounds from African flora showing anti-cancer and/or cytotoxic activities, which have been tested in vitro and in vivo. This corresponds to 400 compounds (from mildly active to very active) covering various compound classes. However, in this part II, we only discussed the three major compound classes which are: flavonoids, alkaloids and terpenoids.

Synergism of Curcumin and Cytarabine in the Down Regulation of Multi-Drug Resistance Genes in Acute Myeloid Leukemia by Krupa Shah, Sheefa Mirza, Urja Desai, Nayan Jain, Rakesh Rawal (128-135).
Background: The aim of the study was to find a role of Curcumin from natural source to overcome drug resistance as well as to reduce cytotoxicity profile of the drug in Acute Myeloid Leukemia patients.
Material and Methods: Primary leukemic cells were obtained from AML patient's bone marrow. These cells were then exposed to different concentration of cytarabine and curcumin to find out IC50 values and also its effect on MDR genes like MDR1, BCRP, LRP and FLT3 by RT-PCR method.
Result & Conclusion: Our results suggested that curcumin down regulates MDR genes. Gene expression was decreased by 35.75, 31.30, 27.97 % for MDR1, LRP, BCRP respectively. In FLT3, it was 65.86 % for wild type and 31.79 % for FLT3-ITD. In addition to this, curcumin has also shown anti-proliferative effect as well as synergistic effect in combination with Cytarabine on primary leukemic cells. Thus, we can conclude that curcumin can be used as MDR modulator as well as chemosensitizer in combination with cytarabine, standard chemotherapeutic drug, to reduce the cytotoxicity profile as IC50 value decreases when treated in combination.