Anti-Cancer Agents in Medicinal Chemistry (Formerly Current Medicinal Chemistry - Anti-Cancer Agents) - Volume 10, Issue 7, 2010

Glioblastoma multiforme (GBM), the most common and deadliest brain cancer in adults, is among the least responsive human cancers to therapy. This dismal prognosis has not been significantly improved in the past decades, despite considerable advance made in the biological understanding of GBM. To address this clinical problem, much effort has been invested in identifying and targeting novel molecular targets and pathways that are critical for GBM biology. Many new therapeutic approaches have been exploited to improve clinical outcome of GBM. The objective of this special issue, therefore, is to summarize some of these exciting findings and to highlight emerging therapeutic targets and approaches for the treatment of GBM patients. Specifically, the Part II of this special issue includes four excellent comprehensive review articles with each covering a unique area of GBM research and therapeutics. The review article by Liu and Lin is focused on signal transducer and activator of transcription 3 (STAT3), an oncogenic transcription factor that is constitutively activated in many human cancers. In recent years, activated STAT3 has been shown to be detected in the majority of GBM tumors and cell lines, playing an essential role in the growth, progression and therapeutic response of GBM cells. STAT3 is also implicated in GBM stem cell biology, as reported by several recent studies. Concurrent with these biological analyses, various preclinical studies have been conducted to examine anti-STAT3 treatments for their ability to suppress GBM growth and to sensitize GBM to chemotherapy. Consequently, much enthusiasm has been generated in this very active field of GBM research. The article by Liu and Lin, therefore, provides an in-depth, timely overview of the nature of the STAT3 pathway, including its upstream regulators and downstream target genes, the pathological impact of STAT3 activation on GBM, and the outcome of various pharmacological approaches that have been developed to target STAT3. Radiation therapy and DNA-damaging chemotherapeutic agents are among the leading treatments for GBM patients. Unfortunately, tumor resistance to these therapies is not uncommon and this is largely attributed to the intrinsic ability of GBM cells to repair therapyinduced DNA damage. The article by Anthony Chalmers summarizes the molecular pathways that mediate tumor response to DNA damage with a major focus on the DNA repair enzyme poly(ADP-ribose) polymerase (PARP). PARP-1 is abundantly expressed in cells, binds to both single and double stranded DNA breaks, and is associated with tumor resistance to DNA-damaging therapies. To overcome this resistance, a number of PARP inhibitors have been developed with several of them being tested in early phase clinical trials. Therefore, Chalmers has assembled a comprehensive review that covers recent promising results showing that combining the PARP inhibitors with chemotherapy and radiotherapy could be an effective strategy that targets GBM. Natural products have been extensively exploited for their preventative and therapeutic effects on various human cancers. Tetrandrine, a bis-benzylisoquinoline alkaloid derived from the Chinese medicinal herb Stephania tetrandra S, has attracted much attention because of its ability to block calcium channel, promote apoptosis and cell-cycle arrest, and to induce oxidative stress. Tetrandrine appears to also affect a number of other physiological processes, such as, immune response and angiogenesis. Importantly, tetrandrine has been recently investigated for its anti-GBM activity and the results were encouraging. In this special tissue, Chen and Tseng provide a timely review on the role and mechanisms of tetrandrine as a sensitizing agent for radiotherapy and chemotherapy in GBM. High degrees of invasiveness and motility are major characteristics of GBM that prevent the tumor from complete resection and this allows for recurrence. Gaining a greater understanding of the molecular pathways that drive GBM invasion and migration will help develop therapeutic strategies that minimize GBM infiltration and thereby, will enable successful surgical removal of the tumor mass. As the final article of this special issue, Adamson and colleagues provide an excellent update on some of the molecular pathways that have been shown to promote GBM cell migration, such as, those mediated by integrins, EGFR, c-Met, PI-3K, PDGFR, VEGF and MMPs. In this review, the authors also summarize the outcome of various preclinical and clinical studies that were designed to target these migration-associated pathways. The four papers summarized above represent the Part II of the thematic issue and also conclude this special tissue of “Anti-Cancer Agents in Medicinal Chemistry”. The eight articles included in this issue, together, have covered an array of different fields of cancer research and treatments. Collectively, more than one thousand studies have been cited which indeed represents the tremendous effort that the contributors have invested in their articles. For this, I would like to express my gratitude to all the contributing authors for their time and outstanding effort. As to the readers, it is my sincere hope that our literature reviews and personal perspectives will introduce you to an exciting area of cancer research and also inspires you to join us in filling the knowledge gaps of one of the deadliest human malignancies and in developing more effective treatments for this devastating disease.

Glioblastoma (GBM) is the most common type of primary malignant brain tumor. Despite advances in surgical resection, radiotherapy and chemotherapy, prognosis remains very poor. Accordingly, recent studies have been focused on the aberrant signal transduction pathways in glioblastoma. Many patient derived primary glioblastomas and cell lines express constitutively activated signal transducers and activators of transcription 3 (STAT3). Here we focused on the recent progresses regarding to the roles of STAT3 in glioblastoma and glioblastoma stem cells (GBM-SCs), the dysregulation of STAT3 in glioblastoma, and targeting STAT3 for glioblastoma therapy.

This article will present the rationale for combining chemical inhibitors of the DNA repair enzyme poly(ADP-ribose) polymerase (PARP) with conventional cytotoxic agents to improve the treatment of glioblastoma. After a brief review of the current therapeutic options for these aggressive tumours, the possible reasons for their resistance to radiation and chemotherapy will be discussed, highlighting the important role of DNA damage response pathways in many key resistance mechanisms. The dose-limiting toxicities associated with radiation and chemotherapy treatment will be described in order to illustrate the importance of tumour specificity in any attempt to increase the effectiveness of conventional treatments. There will then be a summary of the reasons why targeting DNA repair pathways might achieve tumour specific sensitization. After a brief summary of the key DNA damage response pathways, the biology, biochemistry and pharmacology of PARP and the existing PARP inhibitors will be presented. The major part of the review will cover the effects of combining PARP inhibitors with radiation and chemotherapy in vitro and in vivo, commenting on the underlying mechanisms and indicating where the data are predictive of tumour specific sensitization. Finally, we will consider specific scenarios where PARP inhibitors might contribute to the treatment of glioblastoma patients, discuss the challenges and opportunities associated with early phase clinical testing of these agents, and describe the clinical trials that are either underway or in development.

Patients with malignant gliomas have poor prognoses, and the majority of the patients have local tumor recurrence after various treatments including surgery, radiotherapy, and chemotherapy. Thus it is mandatory to develop better therapies for treatment of these malignant brain tumors. Tetrandrine, a bisbenzylisoquinoline alkaloid, has antitumor effects against some cancers. Tetrandrine affects the cell cycle, production of reactive oxygen species, mitogen-activated protein kinase activity, and reverses multidrug resistance in various cancer cells. Since tetrandrine is a highly lipid-soluble and hydrophobic molecule with a low molecular weight, it may cross the blood brain barrier; thus, it could be used for the treatment of gliomas. Tetrandrine inhibits the large-conductance, calcium-activated potassium (BK) channels and the expression of BK channel has a positive correlation with tumor malignancy grade in human gliomas. Furthermore, tetrandrine also exerts cytotoxic effects, and induces apoptosis and radiosensitization in glioma cells by elimination of radiation-induced cell cycle perturbation. It also has anti-angiogenesis effects in gliomas, and exerts an antitumor effect on subcutaneous and intracerebral gliomas. Tetrandrine is a radiosensitizer and also a multidrug resistance reversing agent. Tetrandrine can probably be combined with radiotherapy or other chemotherapeutic agents to treat gliomas. Nonetheless, it is important to determine the balance between the safety and efficacy of tetrandrine in patients with malignant gliomas before any clinical application.

Glioblastoma multiforme (GBM) is one of the most common and most aggressive types of primary brain tumors in humans. Even with aggressive surgical resections using state of the art preoperative and intraoperative neuroimaging, along with the most recent techniques in radiotherapy and chemotherapy, the prognosis for GBM patients remains dismal. Survival after diagnosis is about 12-14 months. The tumor cells which already have migrated into normal brain tissue beyond the surgical resection margin account for the inability to effectively treat this tumor. Understanding how to control the migration of GBM cells is paramount to future therapies. In this review, we will focus on the emerging targets and agents which are being exploited to inhibit the migration of glioma cells in GBM.

Tetracyclines have been long known for their antimicrobial role. They are one of the most widely used antibiotics in clinical practice since last 5 decades. Recently their role as matrix metalloproteinase inhibitor and in apoptosis has widely attracted attention in biological field. Of them, doxycycline is one with long duration of actions and has recently been shown to have various anti-cancer properties, especially cytotoxic and anti-proliferative activities. Here, we systematically reviewed the role of doxycycline in the mitochondrial mediated apoptosis in various tissues. MEDLINE and EMBASE databases were searched using a formal search strategy with definite inclusion and exclusion criteria. Data extraction was performed for each included study using a custom designed data extraction form. A total of 81 references were identified through MEDLINE and 5 were identified through EMBASE. 74 references from MEDLINE and all 5 in EMBASE were excluded through reading titles, abstracts and full text. In total, 7 studies fulfilled inclusion criteria. Following systematic review of these studies, we concluded that doxycycline induces apoptosis through mitochondrial mediated pathway in different tissue cells however it may be cell specific. The caspase independent apoptosis as one of the mechanisms of actions of doxycycline needs further studies for better understanding.

Bisdioxopiperazine (Biz) compounds, including ICRF-154 and razoxane (ICRF-159, Raz), are anticancer agents developed in the UK specifically targeting tumor metastases. Further three bisdioxopiperazine derivatives, bimolane (Bim), probimane (Pro) and MST- 16, have been synthesized at the Shanghai Institute of Materia Medica, Chinese Academy of Sciences, PR China after 1980. Since metastases, the prevailing deadliest pathologic feature of cancer in clinics, have been the main obstacle in cancer therapy, antimetastatic effects and mechanisms of Biz compounds are interesting and significant topics of all time for researchers undergoing the investigations of metastases biology, treatments and patho-physiology. This review addresses and highlights the different inhibitions against metastases in vivo and molecular mechanisms in vitro of Biz compounds especially relating to the inhibitions of tumor metastasis including pathways of inhibitions against angiogenesis, topoisomerase II, calmodulin, sialic acid, fibrinogen, cell-movement and so on. We argue hererin that the systematic exploration of antimetastatic activity and mechanisms of Biz compounds seems to be a shortcut for a final solution of cancer therapy in the future.

Mammalian target of rapamycin (mTOR) is a central controller of cell growth, proliferation, metabolism and angiogenesis. mTOR signaling is often dysregulated in various human diseases and thus attracts great interest in developing drugs that target mTOR. Currently it is known that mTOR functions as two complexes, mTOR complex 1/2 (mTORC1/2). Rapamycin and its analogs (all termed rapalogs) first form a complex with the intracellular receptor FK506 binding protein 12 (FKBP12) and then bind a domain separated from the catalytic site of mTOR, blocking mTOR function. Rapalogs are selective for mTORC1 and effective as anticancer agents in various preclinical models. In clinical trials, rapalogs have demonstrated efficacy against certain types of cancer. Recently, a new generation of mTOR inhibitors, which compete with ATP in the catalytic site of mTOR and inhibit both mTORC1 and mTORC2 with a high degree of selectivity, have been developed. Besides, some natural products, such as epigallocatechin gallate (EGCG), caffeine, curcumin and resveratrol, have been found to inhibit mTOR as well. Here, we summarize the current findings regarding mTOR signaling pathway and review the updated data about mTOR inhibitors as anticancer agents.