Medicinal chemistry and chemical biology of new generation taxane antitumor agents

P-glycoprotein (P-GP)-based multidrug resistance (MDR) and undesirable side effects are significant drawbacks to the clinical use of paclitaxel and docetaxel. Extensive SAR studies of taxanes in these laboratories led to the discovery of new generation taxanes that are highly active against not only drug-sensitive but also drug-resistant human cancer cell lines as well as tumor xenografts in mice. One of these second generation taxanes, SB-T-110131 (IDN5109), exhibited excellent pharmacological profile in the preclinical studies and has been selected for clinical development (recoded as Bay 59-8862), which is currently in the phase II clinical trials. Bay 59-8862 is orally active with high bioavailability, showing excellent activity against a variety of drug-resistant tumors. "Advanced second generation taxanes" show essentially no difference in cytotoxicity against drug-resistant and drug-sensitive cell lines, virtually overcoming MDR. Photoaffinity labeling of P-GP using photoreactive radiolabeled paclitaxel analogs has disclosed the paclitaxel-binding domain of P-GP. Highly efficient taxane-based MDR reversal agents (TRAs) have also been developed, which can recover the cytotoxicity of paclitaxel to practically the original level against paclitaxel-resistant MDR expressing cancer cells. Highly promising results have emerged from the study of taxane-monoclonal antibody (MAb) immunoconjugates, which have been proved to specifically deliver extremely cytotoxic agents to tumor in an animal model.     

Microtubule assembly dynamics: an attractive target for anticancer drugs

Microtubules, composed of alphabeta tubulin dimers, are dynamic polymers of eukaryotic cells. They play important roles in various cellular functions including mitosis. Microtubules exhibit differential dynamic behaviors during different phases of the cell cycle. Inhibition of the microtubule assembly dynamics causes cell cycle arrest leading to apoptosis; thus, qualifying them as important drug targets for treating several diseases including cancer, neuronal, fungal, and parasitic diseases. Although several microtubule-targeted drugs are successfully being used in cancer chemotherapy, the development of resistance against these drugs and their inherent toxicities warrant the development of new agents with improved efficacy. Several antimicrotubule agents are currently being evaluated for their possible uses in cancer chemotherapy. Benomyl, griseofulvin, and sulfonamides have been used as antifungal and antibacterial drugs. Recent reports have shown that these drugs have potent antitumor potential. These agents are shown to inhibit proliferation of different types of tumor cells and induce apoptosis by targeting microtubule assembly dynamics. However, unlike vincas and taxanes, which inhibit cancer cell proliferation in nanomolar concentration range, these agents act in micromolar range and are considered to have limited toxicities. Here, we suggest that these drugs may have a significant use in cancer chemotherapy when used in combination with other anticancer drugs.     

Taxanes, microtubules and chemoresistant breast cancer

The taxanes, paclitaxel and docetaxel are microtubule-stabilizing agents that function primarily by interfering with spindle microtubule dynamics causing cell cycle arrest and apoptosis. However, the mechanisms underlying their action have yet to be fully elucidated. These agents have become widely recognized as active chemotherapeutic agents in the treatment of metastatic breast cancer and early-stage breast cancer with benefits gained in terms of overall survival (OS) and disease-free survival (DFS). However, even with response to taxane treatment the time to progression (TTP) is relatively short, prolonging life for a matter of months, with studies showing that patients treated with taxanes eventually relapse. This review focuses on chemoresistance to taxane treatment particularly in relation to the spindle assembly checkpoint (SAC) and dysfunctional regulation of apoptotic signaling. Since spindle microtubules are the primary drug targets for taxanes, important SAC proteins such as MAD2, BUBR1, Synuclein-gamma and Aurora A have emerged as potentially important predictive markers of taxane resistance, as have specific checkpoint proteins such as BRCA1. Moreover, overexpression of the drug efflux pump MDR-1/P-gp, altered expression of microtubule-associated proteins (MAPs) including tau, stathmin and MAP4 may help to identify those patients who are most at risk of recurrence and those patients most likely to benefit from taxane treatment.     

Immuno-enhancing actions of carnosine and homocarnosine

Immuno-enhancing actions of carnosine, beta-alanine, homocarnosine, and gamma-aminobutyric acid were studied in ddY mice by evaluating plaque-forming cell reaction against sheep red blood cells. Animals were administered the test agents in prior to, or simultaneously with, various treatments that are known to reduce immune function such as administration of the anti-tumor agents, mitomycin C and 5-fluorouracil, immunosuppressant cyclophosphamide, antiinflammatory agent hydrocortisone, or cancer implantation and gamma-irradiation. Experiments were performed also in aged mice with reduced immune function. The administration of these drugs showed non-specific immuno-enhancing effects under all conditions examined and on all cell groups that may have been affected by these immunosuppressive stimulus.     

Paclitaxel may inhibit autoimmune diseases by sparing or increasing the number of CD4(+) CD25(+) regulatory T cells

Paclitaxel, a representative of taxanes, exhibits cytotoxic effects against a broad range of tumors. Strikingly, an emerging body of data suggests that paclitaxel also exerts effects on immune system by stimulating anti-tumor and anti-autoimmunity effects, supporting the idea that paclitaxel suppresses tumor through several mechanisms and not solely through inhibiting cell division. Based on the accumulating data, we hypothesized that paclitaxel may inhibit autoimmune diseases by sparing or actively increasing the number of CD4(+) CD25(+) Treg cells. The hypothesis, if proved to be correct, will significantly improve our understanding of the tumor immunity, autoimmunity and its related pathological effects. It will influence our choice on immunosuppressive drugs for cancer patients with autoimmune diseases. It will also impact the immunotherapy for tumors.     

2011: the immune hallmarks of cancer

Ten years after the publication of the position paper “The hallmarks of cancer” (Hanahan and Weinberg Cell 100:57–70, 2000), it has become increasingly clear that mutated cells on their way to giving rise to a tumor have also to learn how to thrive in a chronically inflamed microenvironment, evade immune recognition, and suppress immune reactivity. Genetic and molecular definition of these three immune hallmarks of cancer offers the opportunity to learn how to deploy specific countermeasures to reverse the situation in favor of the immune system and, eventually, the patient. This new information could be channeled to address what seem to be the three major hallmarks for the immune control of cancer progression: effective procedures to activate immune reactivity; characterization of not-disposable oncoantigens; and counteraction of immune suppression.     

Contribution of myeloid-derived suppressor cells to tumor-induced immune suppression, angiogenesis, invasion and metastasis

Growing evidence suggests that myeloid-derived suppressor cells (MDSCs), which have been named "immature myeloid cells" or "myeloid suppressor cells" (MSCs), play a critical role during the progression of cancer in tumor-bearing mice and cancer patients. As their name implies, these cells are derived from bone marrow and have a tremendous potential to suppress immune responses. Recent studies indicated that these cells also have a crucial role in tumor progression. MDSCs can directly incorporate into tumor endothelium.They secret many pro-angiogenic factors as well. In addition, they play an essential role in cancer invasion and metastasis through inducing the production of matrix metalloproteinases (MMPs), chemoattractants and creating a pre-metastatic environment. Increasing evidence supports the idea that cancer stem cells (CSCs) are responsible for tumorigenesis, resistance to therapies, invasion and metastasis.Here, we hypothesize that CSCs may "hijack" MDSCs for use as alternative niche cells, leading to the maintenance of stemness and enhanced chemo- and radio-therapy resistance. The countermeasure that directly targets to MDSCs may be useful for against angiogenesis and preventing cancer from invasion and metastasis. Therefore, the study of MDSCs is important to understand tumor progression and to enhance the therapeutic efficacy against cancer.     

Environmental contaminants in pathogenesis of breast cancer

This review is an attempt to comprehend the diverse groups of environmental chemical contaminants with a potential for pathogenesis of breast cancer, their probable sources and the possible mechanisms by which these environmental contaminants act and interplay with other risk factors. Estrogens are closely related to the pathogenesis of breast cancer. Oxidative catabolism of estrogen, mediated by various cytochrome P450 enzymes, generates reactive free radicals that can cause oxidative damage. The same enzymes of estrogenic metabolic pathways catalyze biological activation of several environmental (xenobiotic) chemicals. Xenobiotic chemicals may exert their pathological effects through generation of reactive free radicals. Breast tissue can be a target of several xenobiotic agents. DNA-reactive metabolites of different xenobiotic compounds have been detected in breast tissue. Many phase I and II xenobiotic metabolizing enzymes are expressed in both normal and cancerous breast tissues. These enzymes play a significant role in the activation/detoxification of xenobiotic and endogenous compounds including estrogens. More than 30 carcinogenic chemicals are present in tobacco smoke; many of them are fat-soluble, resistant to metabolism and can be stored in breast adipose tissue. Similarly, pesticides are also known to cause oxidative stress; while some act as endocrine disruptor, some are shown to suppress apoptosis in estrogen sensitive cell lines. Reports have shown an association of smoking (both active and passive) and pesticides with breast cancer risk. However, the issues have remained controversial. Different mutagenic substances that are generated in the cooking process e.g., heterocyclic amines and polycyclic aromatic hydrocarbons (PAHs) can be a threat to breast tissue. PAHs and dioxins exert their adverse effects through the aryl hydrocarbon receptor (AhR), which activates several genes involved in the metabolisms of xenobiotic compounds and endogenous estrogens. These chemicals also induce AhR-dependent mitochondrial dysfunction. Many of the environmental pollutants suppress the immune system, which are implicated to risk. A better understanding about the biological effects of different environmental carcinogenic compounds and determination of their impact on rising incidence of breast cancer will be beneficial in improving preventive policy against breast cancer.     

A paradoxical role for myeloid-derived suppressor cells in sepsis and trauma

Myeloid-derived suppressor cells (MDSCs) are a heterogenous population of immature myeloid cells whose numbers dramatically increase in chronic and acute inflammatory diseases, including cancer, autoimmune disease, trauma, burns and sepsis. Studied originally in cancer, these cells are potently immunosuppressive, particularly in their ability to suppress antigen-specific CD8(+) and CD4(+) T-cell activation through multiple mechanisms, including depletion of extracellular arginine, nitrosylation of regulatory proteins, and secretion of interleukin 10, prostaglandins and other immunosuppressive mediators. However, additional properties of these cells, including increased reactive oxygen species and inflammatory cytokine production, as well as their universal expansion in nearly all inflammatory conditions, suggest that MDSCs may be more of a normal component of the inflammatory response ("emergency myelopoiesis") than simply a pathological response to a growing tumor. Recent evocative data even suggest that the expansion of MDSCs in acute inflammatory processes, such as burns and sepsis, plays a beneficial role in the host by increasing immune surveillance and innate immune responses. Although clinical efforts are currently underway to suppress MDSC numbers and function in cancer to improve antineoplastic responses, such approaches may not be desirable or beneficial in other clinical conditions in which immune surveillance and antimicrobial activities are required.     

Renewed interest in cancer immunotherapy with the tumor necrosis factor superfamily molecules

Molecules belonging to the Tumor Necrosis Factor (TNF) and TNF receptor superfamilies have explosively expanded through the era of genomics and bioinformatics. Biological investigations of these molecules have explored their potency as attractive targets for cancer therapy. Anti-tumor mechanisms mediated by TNF superfamily molecules (TNFSF) could be classified into direct actions onto tumor cells and indirect effects through immune or non-immune components of tumor-bearing host. In this review, we focus on TRAIL, CD40, 4-1BB (CD137), and LIGHT as promising molecules to mediate powerful and selective anti-tumor responses, and summarize their unique effector mechanisms. In addition, optimal approaches to manipulate these molecules for cancer therapy are also discussed. We try to provide an insight into a role of TNFSF in cancer therapeutics and highlight each of their potency to be an important player in anti-cancer strategies.     

Evolution of adjuvant chemotherapy of breast cancer from Bonadonna to the taxanes

The author summarizes the progress of adjuvant chemotherapy of breast cancer from the classical Bonadonna-type CMF over the anthracyclines to the taxanes. The CMF regimen represented the prototype of combination chemotherapy which significantly improved early and long term results. After 20 years the patients given adjuvant combination chemotherapy with CMF had significantly better rates of relapse-free survival (p<0.001) and overall survival (p=0.03) compared with no chemotherapy. 6 cycles of CMF was the gold standard of adjuvant chemotherapy in breast cancer for decades. The Milan research group decided in the early 1980s to challange this popular CMF combination by introducing doxorubicin within the adjuvant program. Compared with standard CMF, anthracyclin-containing regimens reduced the annual risk of recurrence by 12% and the annual risk of death by 11%, equating to a 3.2% absolute reduction in recurrence and a 2.7% absolute reduction in mortality at 5 years. This small but real difference seen with regimens containing three or more agents (e.g. CEF and CAF, FAC, FEC, etc.), whereas 4 cycles of 2-drug regimens (e.g. AC or EC) appears to be equivalent to 6 cycles of CMF. Among the novel chemotherapeutic drugs introduced in the 1990s the taxanes have emerged as the most powerful compounds in breast cancer. Several large, adjuvant clinical trials are currently ongoing or have recently completed accrual. The available results from innumerable clinical studies are still inconclusive and do not support the routine use of taxanes in the adjuvant setting - with the exception of the BCIRG 001 docetaxel trial, in which significant improvement was documented in disease free survival with 6 x TAC compared with 6 x FAC (82% vs 74%). Studies on the effect of the new trastuzumab (an antibody against the extracellular domain of the HER2) in adjuvant setting was initiated in early 2000. The Herceptin adjuvant trial programme is extensive, involving more than 12,000 patients worldwide. This trials will potentially offer many women with HER2-positive disease the chance of improved survival.     

Pharmaceutically active secondary metabolites of microorganisms

The antibiotics have been useful in our battles against infectious bacteria and fungi for over 50 years. However, many antibiotics are used commercially, or are potentially useful, in medicine for activities other than their antibiotic action. They are used as antitumor agents, immunosuppressive agents, hypocholesterolemic agents, enzyme inhibitors, antimigraine agents, and antiparasitic agents. A number of these products were first discovered as antibiotics which failed in their development as such, or as mycotoxins. In addition to the above alternative applications, new powerful antibiotics have been discovered and commercialized in recent years and others are in clinical testing at the moment. A few successful secondary metabolites appear to have no antibiotic activity. The recently increased development of resistance to older antibacterial and antifungal drugs is being met with the use or clinical testing of older, underutilized or previously nondeveloped narrow-spectrum antibacterial products as well as powerful semisynthetic antifungal agents. Received: 28 December 1998 / Received revision: 26 April 1999 / Accepted: 1 May 1999     

Sensitivity of parasites to free radical damage by antiparasitic drugs

Over the last few years a remarkable progress has been made in the understanding of parasites biochemistry, molecular biology, and immunology. This progress is especially encouraging in that emphasis on drug development is shifting from random screening towards a more rational approach. A number of peculiar aspects characteristic of parasites which are not present in other organisms and that might be exploitable for the design of specific agents have been described recently. One of these aspects is their deficiency in defense mechanisms against oxygen toxicity. Catalase is absent in many parasites. Distinct superoxide dismutases have been detected and specific inhibitors of these enzymes have been investigated. Glutathione is absent in some anaerobic protozoa. Peroxidase and reductase activities dependent on a glutathione-spermidine cofactor termed trypanothione have been detected in several trypanosomatids and apparently replace the glutathione peroxidase-glutathione reductase system of other eukaryotic cells. Free radical intermediates have been shown to be involved in the reaction of enzymes present in anaerobic protozoa. In addition, a number of antiparasitic agents have been shown to exert their actions through a free radical metabolism: nitro compounds used against trypanosomatids, anaerobic protozoa and helminths; crystal violet used in blood banks to prevent blood transmission of Chagas' disease; the antimalarial primaquine, chloroquinine, and quinhasou; and quinones active in vitro and in vivo against different parasites.     

The effect of oxidizing agents on cell division and shape

Certain oxidizing agents such as vitaminK(VK) and lipid peroxides were found to suppress an increase in cytoplasmic Ca2+ concentration by growth factors, and inhibit on cell proliferation. These oxidizing agents induced a marked change in cell shape. In a detailed analysis of each phase in the cell cycle, the inhibition of an increase in cytoplasmic Ca2+ and cell division occurred only when the agents were added at G0/G1 phase. The addition to S or M phase cells did not influence in cytoplasmic Ca2+ and cell division. These experimental results suggest that these oxidizing agents may inhibit the transfer of stimulation signals from growth factors by acting on cell membrane sites and suppress subsequent DNA replication and mitotic division.     

Immunonutrition and cancer

The immune system is the body's primary defence against invading pathogens, non-self components and cancer cells. Inflammatory processes, including the release of pro-inflammatory cytokines and formation of reactive oxygen and nitrogen species, are an essential part of these processes. Although such actions are usually followed rapidly by anti-inflammatory effects, excessive production of pro-inflammatory cytokines, or their production in the wrong biological context may lead to situations of chronic inflammation. Whether such conditions arise as a result of exogenous chemicals, invading pathogens or disease processes, the long-term implications include an increased risk of cancer. A number of nutrients have the ability to modulate immune response and counter inflammatory processes. Zinc, epigallocatechin galate (EGCG), omega-3 polyunsaturated fatty acids and probiotics all act differently to modulate immune response, but all appear to have the potential to protect against cancer development and progression. We suggest that immunonutrition may provide a less invasive alternative to immunotherapy in protection against cancers associated with chronic inflammation.     

Docetaxel promotes the generation of anti-tumorigenic human macrophages

The taxanes Docetaxel and Paclitaxel are two of the standard chemotherapies for patients with metastatic breast cancer. The functional effect of Docetaxel and Paclitaxel on human innate immune cells of the myeloid lineage is not well established, nor is the effects these agents have on differentiation of monocytes into macrophages and dendritic cells. Therefore, the aim with this project was to determine the effects of Docetaxel and Paclitaxel on primary human monocyte differentiation, activation and function. For this purpose, primary human monocytes were isolated from healthy donors and cultured with or without Docetaxel and Paclitaxel. We found that Docetaxel promoted the differentiation of primary human monocytes into pro-inflammatory macrophages with an M1 phenotype and an ability to present antigens to T cells. Monocytes treated with Docetaxel also displayed an elevated secretion of IL-8 and IL-1β, but did not promote generation of monocytic myeloid-derived suppressor cells. In conclusion, Docetaxel appears to have an immune stimulatory effect that would be beneficial for an anti-tumorigenic type of immune response, whereas Paclitaxel seems to have less effect on myeloid cells.     

Synthesis and biological evaluation of helioxanthin analogues

Helioxanthin and analogues have been demonstrated to suppress gene expression of human hepatitis B virus. In the continuous attempt to optimize antiviral activity, various structural motifs were grafted on the helioxanthin scaffold. Many such analogues were synthesized and evaluated for their anti-hepatitis B virus activity. Structure–activity relationships of these helioxanthin derivatives are also discussed. Among these new compounds, 15 exhibits the highest activity against HBV (EC₅₀ = 0.06 μM). This compound can suppress viral surface antigen and DNA expression. Furthermore, viral RNA is also diminished while the core promoter is deactivated upon treatment by 15. A plausible working mechanism is postulated. Our results establish helioxanthin lignans as potent anti-HBV agents with unique mode of action. Since their antiviral mechanism is distinct from current nucleoside/nucleotide drugs, helioxanthin lignans constitute a potentially new class of anti-HBV agents for combination therapy.     

Chemopreventive agent-induced modulation of death receptors

The goals of chemoprevention of cancer are to inhibit the initiation or suppress the promotion and progression of preneoplastic lesions to invasive cancer through the use specific natural or synthetic agents. Therefore, a more desirable and aggressive approach is to eliminate aberrant clones by inducing apoptosis rather than merely slowing down their proliferation. The increased understanding of apoptosis pathways has directed attention to components of these pathways as potential targets not only for chemotherapeutic but also for chemopreventive agents. Activation of death receptors triggers an extrinsic apoptotic pathway, which plays a critical role in tumor immunosurveillance. An increasing number of previously identified chemopreventive agents were found to induce apoptosis in a variety of premalignant and malignant cell types in vitro and in a few animal models in vivo. Some chemopreventive agents such as non-steroidal anti-inflammatory drugs, tritepenoids, and retinoids increase the expression of death receptors. Thus, understanding the modulation of death receptors by chemopreventive agents and their implications in chemoprevention may provide a rational approach for using such agents alone or in combination with other agents to enhance death receptor-mediated apoptosis as a strategy for effective chemoprevention of cancer.     

Clinical applications of retinoids in cancer medicine

The retinoids are compounds structurally related to vitamin A. The most extensively studied agents in cancer medicine include all-trans-retinoic acid, 9-cis-retinoic acid, and 13-cis-retinoic acid. In addition to several described immune regulatory functions, these agents may exert their antineoplastic effects through the regulation of tumor suppressor genes such as RAR-beta2. The survival benefit provided to patients with acute promyelocytic leukemia (APL) after induction therapy with all-trans RA and the responses experienced by patients with cutaneous lesions from Kaposi's sarcoma and cutaneous T cell lymphoma treated with 9-cis RA and a selective rexinoid--bexarotene--respectively, led to their approval by the Food and Drug Administration during the last decade. As chemopreventive agents, retinoids have proven to effectively regress laryngeal papillomatosis and oral leukoplakia lesions. The ability of 13-cis-RA to prevent second primary malignancies in patients with carcinoma of the head and neck has also been demonstrated. Unfortunately, this intervention did not affect the primary tumor recurrence rates. The toxicity and efficacy of retinoids administered in combination with other biological and cytotoxic agents have also been explored in patients with renal cell carcinoma, breast cancer, myelodysplasia, prostate, cervix, and other malignancies with a broad range of reported responses. Further characterization of the molecular processes modulated by these agents will serve to better define their role in the prevention and treatment of human cancer and to tailor specific targeted therapies in combination with other compounds. Newer and more selective retinoids and rexinoids are completing phase I and phase II studies and hold promising.