Small Molecule Anticancer Drugs Research Articles

Transmembrane delivery of anticancer drugs through self-assembly of cyclic peptide nanotubes.

Breaking the natural barriers of cell membranes achieves fast entry of therapeutics, which leads to enhanced efficacy and helps overcome multiple drug resistance. Herein, transmembrane delivery of a series of small molecule anticancer drugs was achieved by the construction of artificial transmembrane nanochannels formed by self-assembly of cyclic peptide (cyclo[Gln-(d-Leu-Trp)4-d-Leu], CP) nanotubes (CPNTs) in the lipid bilayers. Our in vitro study in liposomes indicated that the transport of molecules with sizes smaller than 1.0 nm, which is the internal diameter of the CPNTs, could be significantly enhanced by CPNTs in a size-selective and dose-dependent manner. Facilitated uptake of 5-fluorouracil (5-FU) was also confirmed in the BEL7402 cell line. On the contrary, CPs could facilitate neither the transport across liposomal membranes nor the uptake by cell lines of cytarabine, a counterevidence drug with a size of 1.1 nm. CPs had a very weak anticancer efficacy, but could significantly reduce the IC50 of 5-FU in BEL7402, HeLa and S180 cell lines. Analysis by a q test revealed that a combination of 5-FU and CP had a synergistic effect in BEL7402 at all CP levels, in S180 at CP levels higher than 64 μg mL(-1), but not in HeLa, where an additive effect was observed. Temporarily, intratumoral injection is believed to be the best way for CP administration. In vivo imaging using (125)I radio-labelled CP confirmed that CPNPTs were completely localized in the tumor tissues, and translocation to other tissues was negligible. In vivo anticancer efficacy was studied in the grafted S180 solid tumor model in mice, and the results indicated that tumor growth was greatly inhibited by the combinatory use of 5-FU and CP, and a synergistic effect was observed at CP doses of 0.25 mg per kg bw. It is concluded that facilitated transmembrane delivery of anticancer drugs with sizes smaller than 1.0 nm was achieved, and the synergistic anticancer effect was confirmed both in cell lines and in vivo through the combinatory use of 5-FU and CP.

Amphiphilic drug–drug assembly via dual-responsive linkages for small-molecule anticancer drug delivery

Amphiphilic drug–drug assembly nanoparticles based on dual-responsive H-bonding-instructed disulfide bonds can release irinotecan and doxorubicin simultaneously in cancer cells for anticancer purposes.

Genetic and Pharmacological Screens Converge in Identifying FLIP, BCL2, and IAP Proteins as Key Regulators of Sensitivity to the TRAIL-Inducing Anticancer Agent ONC201/TIC10.

ONC201/TIC10 is a small-molecule inducer of the TRAIL gene under current investigation as a novel anticancer agent. In this study, we identify critical molecular determinants of ONC201 sensitivity offering potential utility as pharmacodynamic or predictive response markers. By screening a library of kinase siRNAs in combination with a subcytotoxic dose of ONC201, we identified several kinases that ablated tumor cell sensitivity, including the MAPK pathway-inducer KSR1. Unexpectedly, KSR1 silencing did not affect MAPK signaling in the presence or absence of ONC201, but instead reduced expression of the antiapoptotic proteins FLIP, Mcl-1, Bcl-2, cIAP1, cIAP2, and survivin. In parallel to this work, we also conducted a synergy screen in which ONC201 was combined with approved small-molecule anticancer drugs. In multiple cancer cell populations, ONC201 synergized with diverse drug classes, including the multikinase inhibitor sorafenib. Notably, combining ONC201 and sorafenib led to synergistic induction of TRAIL and its receptor DR5 along with a potent induction of cell death. In a mouse xenograft model of hepatocellular carcinoma, we demonstrated that ONC201 and sorafenib cooperatively and safely triggered tumor regressions. Overall, our results established a set of determinants for ONC201 sensitivity that may predict therapeutic response, particularly in settings of sorafenib cotreatment to enhance anticancer responses.

SY10-3 - Factors Influencing the Onset of Chemotherapy-Induced Adverse Events Including Drug-Drug Interaction

It is important for cancer chemotherapy to maintain effective response with minimizing undesired drug effects. Individual differences of pharmacokinetics (PK) and pharmacodynamics (PD) of anticancer drugs contribute a great deal to the development of adverse events. With regard to PK change, decrease in renal clearance due to renal failure or drug-drug interaction is one of the most serious problem for drugs mainly excreted by the kidney. Folic acid analogs are typical drugs excreted by the kidney. Recently, we indicated that pemetrexed, one of the folic acid analogs, is a superior substrate to methotrexate for hOAT3 (SLC22A8), and nonsteroidal anti-inflammatory drugs (NSAIDs) could cause drug-drug interaction via renal tubular transport by OAT3 when attaining their high plasma concentrations 1). Incidentally, almost all of small molecule anticancer drugs, which targets intracellular signaling pathway, are metabolized by hepatic cytochrome P450 (CYP) 3A. Strong inhibitors of CYP3A are sometimes used together with the small molecular drugs and increase their plasma concentration, which results in increased risk of toxicities. We previously showed that strong CYP3A inhibitor, itraconazole, appeared to exacerbate peripheral neuropathy and thrombocytopenia caused by bortezomib, a proteasome inhibitor 2). Furthermore, we found out that carboplatin-induced severe allergy after multiple dose of the drugs accompanied the change in immunological reaction, which was obviously confirmed by basophil activation 3), whereas a toxicological study focused on PD change during chemotherapy is still limited.In this symposium, we will summarize our recent findings about the risk of chemotherapy-induced toxicities, which involves the changes in PK/PD of anticancer drugs in clinical settings.1) Kurata T et al., Drug Metab Pharmacokinet (2014)2) Iwamoto T et al., Pharmacotherapy (2010)3) Iwamoto T et al., Biol Pharm Bull (2012)

Abstract 2509: Hsp90-inhibitor drug conjugates (HDC): Novel tumor-selective drug delivery platform with unprecedented anticancer activity

Abstract Background: Various strategies have been used to make chemotherapeutic compounds more tumor selective in order to increase their safety and efficacy, but they were met with only limited success. Antibody Drug Conjugates (ADCs) and folate receptor mediated drug delivery (FRDC) are the emerging concepts in the drug delivery field, but they are limited to high potent toxins and narrow sets of indications. We established a novel tumor-directed drug delivery platform technology based on the unique property of Hsp90 inhibitors. One prominent feature of Hsp90 inhibitors is their ability to be retained selectively in tumor cells for a prolonged period of time. The difference in residency time in tumor against plasma and normal tissues is 10-25 fold. Moreover, the chaperone protein Hsp90 is overexpressed 2-3 fold in tumor compared to normal tissues. Combining the overexpression Hsp90 and longer residency of its inhibitors in tumor, a strategy to link anticancer drugs to an Hsp90 inhibitor, where the attached “payload” is released in the tumor selectively for prolonged periods, was conceived. Results: Though the HDC concept is applicable to most small molecule anticancer drugs, we chose a common topoisomerase-1 inhibitor (SN-38) for proof-of-concept studies. More than 100 Hsp90 inhibitor/SN38 conjugates were synthesized; we chose STA-12-8666 as our lead molecule based on its in vitro and in vivo pharmacokinetic properties. The conjugate binds strongly to Hsp90 as determined by client protein degradation assays and has good stability in plasma of several species (human>rat>mouse). In xenograft tumor tissue distribution studies, we demonstrate that mice dosed once weekly with 50 mg/kg STA-12-8666 clear the parental HDC and its cleavage products, SN-38 and the Hsp90 inhibitor, from plasma and normal tissue within 24 hr. However, we detected 0.6 µM and 0.3 µM SN-38 in tumor at 24h and 48h, respectively. SN-38 was not detected in tumor at 24h or 48h with an equivalent dose of the SN-38 prodrug, irinotecan. Xenograft studies using multiple cell lines demonstrated superior efficacy for STA-12-8666 compared to irinotecan. For example, in MCF-7 breast cancer xenografts, STA-12-8666 produced 70% regression in tumor volume compared to moderate tumor growth inhibition by irinotecan with no regression. Similar results were observed in in colon, SCLC, ovarian, bladder, NSCLC, melanoma models. Preliminary toxicological evaluation of STA-12-8666 resulted in better or comparable toxicities to that of irinotecan. Conclusion: We designed a novel tumor-directed drug delivery platform by conjugating previously validated small molecule chemotherapeutics to HSP90 inhibitors. Our lead candidate STA-12-8666, has great tissue distribution profile, superior in vivo antitumor activity and better safety profile than the active control irinotecan, warranting its clinical evaluation. Citation Format: Dinesh Chimmanamada, David Proia, Takayo Inoue, Luisa Shin Ogawa, Suqin He, Manuel Sequeira, Donald Smith, John-Paul Jimenez, Chaohua Zhang, Jim Sang, Jaime Acquaviva, Masazumi Nagai, Yuan Liu, Josephine Ye, Dan Zhou, Andrew Sonderfan, Ritu Singh, Noriaki Tatsuta, Teresa Przewloka, Jun Jiang, Junyi Zhang, Weiwen Ying. Hsp90-inhibitor drug conjugates (HDC): Novel tumor-selective drug delivery platform with unprecedented anticancer activity. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2509. doi:10.1158/1538-7445.AM2014-2509

Abstract 660: Engineering strategies to control stoichiometry, site of conjugation, serum stability and effector functions of antibody-drug conjugates

Abstract A promising approach to enhance the antitumor activity of antibodies and reduce the systemic toxicity of small molecule anti-cancer drugs is to covalently attach the small molecule to the antibody thus forming antibody drug conjugates (ADCs). Conventionally, ADCs are produced by chemical conjugation of drugs to antibodies through either lysine side chain amines or native cysteine sulfhydryl groups generated by reduction of interchain disulfide bonds. Both of these methods yield heterogeneous conjugates with complex biophysical properties. To limit these liabilities, we have designed, characterized, and validated antibody variants, which allow precise control of the site of conjugation and the drug load; such as two and/or four drugs per antibody can be site-specific conjugated. These engineered antibody variants can be efficiently and site-specifically conjugated with drug payloads at milligram and gram scales to yield homogenous ADC products. Engineered antibody variants described here retain antigen-binding affinities, FcRn binding, and have biochemical, biophysical and manufacturability properties similar to their non-engineered parent antibodies. Upon conjugation to highly cytotoxic drugs with anti-mitotic and/or DNA alkylating activities, the antibody variants have potent in vitro and in vivo anti-tumor activity. Furthermore, we describe ADCs vehicles that provide efficient scaffolds for site-specific conjugation of drugs while offering the opportunity to minimize off-target toxicities often observed with ADCs as a result of their binding to cells expressing Fc-gamma receptors. Finally, we show the impact of the identified sites for drug conjugation on the in vivo pharmacokinetic and safety profile of ADCs in rats. Our strategies for engineering ADCs with defined sites for conjugation, controlled drug loads, potentially decreased off-target toxicity, and optimal serum stability are broadly applicable to any full-length IgG or Fc-containing therapeutics as they involve the Fc constant domain of the antibody. Citation Format: Nazzareno Dimasi, Ryan Fleming. Engineering strategies to control stoichiometry, site of conjugation, serum stability and effector functions of antibody-drug conjugates. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 660. doi:10.1158/1538-7445.AM2014-660

Norcantharidin enhances ABT-263-mediated anticancer activity in neuroblastoma cells by upregulation of Noxa

Neuroblastoma is an aggressive childhood disease. Even with intensive conventional treatments, the long term survival rate for children with neuroblastoma remains less than 40%, highlighting the importance of finding new therapies. Bcl-2 family proteins play crucial roles in survival, proliferation and chemotherapeutic resistance of neuroblastoma cells. Therefore, targeting Bcl-2 with small molecule inhibitor ABT-263 could be a novel strategy for treatment of neuroblastoma. However, previous studies indicated that most neuroblastoma cell lines are resistant to ABT-263-mediated apoptosis. Thus, it is crucial to discover approaches that could overcome ABT-263 resistance. In this study, we examined the anticancer activity of ABT-263 in combination with norcantharidin (NCTD), a small-molecule anticancer drug derived from a traditional Chinese medicine, in human malignant neuroblastoma cells. We found that NCTD substantially enhanced ABT-263-mediated apoptosis induction, cell viability inhibition, and clonal formation inhibition in neuroblastoma SH-SY5Y and CHLA-119 cell lines. Moreover, the combination anticancer activity was accompanied by upregulation of Noxa, and was associated with characteristics of mitochondrial apoptosis signaling, such as cytosolic release of cytochrome c, activation of caspase-9,-3, and cleavage of PARP. Notably, we observed that knockdown of Noxa significantly attenuated cell death induction by cotreatment with ABT-263 and NCTD, indicating Noxa essentially contributes to the combination anticancer effect. Collectively, our study demonstrated that NCTD could overcome ABT-263-resistance in neuroblastoma cells, and suggested that combinational treatment of ABT-263 with NCTD might be a novel therapeutic option for children with neuroblastoma.

Systemic co-delivery of doxorubicin and siRNA using nanoparticles conjugated with EGFR-specific targeting peptide to enhance chemotherapy in ovarian tumor bearing mice

This aim of this study was to develop peptide-conjugated nanoparticles (NPs) for systemic co-delivery of siRNA and doxorubicin to enhance chemotherapy in epidermal growth factor receptor (EGFR) high-expressed ovarian tumor bearing mice. The active targeting NPs were prepared using heptapeptide-conjugated poly(d,l-lactic-co-glycolic acid)–poly(ethylene glycol). The particle sizes of peptide-free and peptide-conjugated NPs were 159.3 ± 32.5 and 184.0 ± 52.9 nm, respectively, with zeta potential −21.3 ± 3.8 and −15.3 ± 2.8 mV. The peptide-conjugated NPs uptake were more efficient in EGFR high-expressed SKOV3 cells than in EGFR low-expressed HepG2 cells due to heptapeptide specificity. The NPs were used to deliver small molecule anticancer drug (e.g., doxorubicin) and large molecule genetic agent (e.g., siRNA). The IC50 of doxorubicin-loaded peptide-conjugated NPs (0.09 ± 0.06 μM) was significantly lower than peptide-free NPs (5.72 ± 2.64 μM). The similar result was observed in siRNA-loaded NPs. The peptide-conjugated NPs not only served as a nanocarrier to efficiently deliver doxorubicin and siRNA to EGFR high-expressed ovarian cancer cells but also increased the intracellular accumulation of the therapeutic agents to induce assured anti-tumor growth effect in vivo.

A Review of Study Designs and Outcomes of Phase I Clinical Studies of Nanoparticle Agents Compared with Small-Molecule Anticancer Agents

Nanoparticles or carrier-mediated agents have been designed to prolong drug circulation time, increase tumor delivery, and improve therapeutic index compared to their small-molecule counterparts. The starting dose for phase I studies of small molecules and nanoparticles anticancer agents is based on the toxicity profile of the most sensitive species (e.g., rat or canine), but the optimal animal model for these studies of nanoparticles is unclear. The objective of this study was to evaluate the design, progression, and outcomes of phase I studies of nanoparticles compared with small-molecule anticancer agents. In preclinical studies, the maximum tolerated dose (MTD) in rats and dogs was evaluated for nanoparticles and their respective small molecules. In phase I clinical trials in patients with advanced solid tumors, the basis for starting dose, the number of dose escalations, number of patients enrolled, and the ratio of MTD to starting dose was determined for nanoparticles and small molecules. The mean ratio of MTD to starting dose in clinical phase I studies was significantly greater for nanoparticles (13.9 ± 10.8) compared with small molecules (2.1 ± 1.1; P = 0.005). The number of dose levels in a clinical phase I study was also significantly greater for nanoparticles (7.3 ± 2.9) compared with small molecules (4.1 ± 1.5; P = 0.008). The degree of dose escalation from starting dose to MTD was significantly greater for nanoparticles as compared with small-molecule anticancer drugs. These findings necessitate the need to identify the most appropriate preclinical animal model to use when evaluating nanoparticles toxicity.

An Alternative Approach for Quantitative Bioanalysis using Diluted Blood to Profile Oral Exposure of Small Molecule Anticancer Drugs in Mice

A quantitative bioanalytical method for pharmacokinetic studies using diluted whole blood from serially bled mice was developed. Oral exposure profiles in mice for five model anticancer compounds dacarbazine, gefitinib, gemcitabine, imatinib, and topotecan were determined following discrete and cassette (five-in-one) dosing. Six micro blood samples per animal were collected and added to a fixed amount of water. This dilution served several purposes: the red blood cells were lysed; an anticoagulant was unnecessary and the fluid volume of diluted sample was sufficient for bioanalytical assays. AUC values obtained from blood concentrations were within twofold for discrete and cassette dosing except for imatinib (2.1-fold difference) and in agreement with those obtained from plasma concentrations after discrete dosing. All compounds were stable in plasma and diluted blood samples for at least 2 weeks at approximately -80°C. Matrix and intermatrix effects were evaluated to ensure robustness and integrity of the bioanalytical assays. This method provides significant process improvement by enhancing efficiency for sample collection and processing and reducing resources (e.g., reduced compound, cost, and animal requirement) compared with conventional methods. Our study demonstrates the applicability of using diluted micro blood samples for small molecule quantitative bioanalysis to support mouse studies in drug discovery.

Amphiphilic starlike dextran wrapped superparamagnetic iron oxide nanoparticle clsuters as effective magnetic resonance imaging probes

Starlike polymers have been widely used in various fields, such as tissue engineering, imaging, gene and drug delivery because of their unique structures and properties. Dextran has long been used as a temporary plasma substitute because of its excellent biocompatibility. In this study, starlike polysaccharide with multiple dextran arms was designed and developed by attaching dextran to a β-cyclodextrin core through click chemistry. Next, starlike dextran was modified with aliphatic chains and these amphiphilic polymers can self-assemble into nanoscale micelles in water, and their critical micelle concentration values (3.7 × 10−8 M) are much lower comparing to its linear analogs (1.7 × 10−7 M), resulting in more stable nanostructures in aqueous environment. These micelles can encapsulate multiple superparamagnetic iron oxide nanoparticles and forming clustering particle nanostructures in water, and the resulting nanocomposites have a high T2 relaxivity of 436.8 Fe mm−1 s−1 under a 1.5T clinical magnetic resonance imaging (MRI) scanner. Further, dual functional probes were developed by loading both superparamagnetic iron oxide nanoparticles and small molecule anticancer drug doxorubicin into polymeric micelles. Multidrug-resistant breast cancer cells MCF-7/Adr treated with these probes can be characterized under MRI.

Design and synthesis of 2(1H)-pyrazinones as inhibitors of protein kinases

Kinase enzymes play a key role in the development and progression of cancer. Inhibitors of deregulated kinases are effective small molecule anticancer drugs. The 2(1H)-pyrazinone heterocycle is a previously unexploited motif that can fulfil the structural requirements for ATP-competitive inhibition of kinases. Rapid solution-phase syntheses of novel 3,5- and 3,6-disubstituted-2(1H)-pyrazinones were developed through selective, sequential substitution of 2,5-dihalo-3-benzyloxypyrazine and 3,5-dihalo-2(1H)-pyrazinone intermediates. Palladium-catalysed cross-couplings and SNAr reactions were used to introduce substituents chosen on the basis of the calculated physicochemical properties of the target pyrazinones. Representative compounds demonstrated good solubility, kinase inhibitory activity and antiproliferative activity in human tumour cells, confirming the suitability of this chemical class as a kinase-focused library.

Interview With Dr You Han Bae: Ligand-mediated Versus ‘passive‘ Targeting Approaches in Nanoparticle Oncology Research

Professor Bae is Associate Editor for the Americas and an Editor of concept papers for the Journal of Controlled Release. He also serves several journals as a member of their editorial boards. His research interests include the rational design of carriers for small-molecule anticancer drugs, genetic materials and proteins, and multifunctional nanotechnology to overcome tumor heterogeneity and multidrug resistance. He is also interested in developing novel preclinical models with increased predictive power. Professor Bae discusses ‘passive’ and ‘active’ targeting approaches to nanoparticle oncology research with Laura Harvey (Commissioning Editor) at Therapeutic Delivery.

Norcantharidin enhances ABT-737-induced apoptosis in hepatocellular carcinoma cells by transcriptional repression of Mcl-1

Small-molecule cell-permeable Bcl-2/Bcl-xL antagonist ABT-737 has recently emerged as a novel cancer therapeutic agent because it potently induces apoptosis in certain cancer cells. However, since ABT-737 binds to Mcl-1 with low affinity, ABT-737-mediated apoptosis signaling is inhibited in hepatocellular carcinoma (HCC) cells and other solid cancer cells due to the elevated expression of Mcl-1. Accordingly, strategies that target Mcl-1 are explored for overcoming ABT-737-resistance. In this study, we reported that Norcantharidin (NCTD), a small-molecule anticancer drug derived from Chinese traditional medicine blister beetle (Mylabris), induced transcriptional repression of Mcl-1 and considerably enhanced ABT-737-triggered cell viability inhibition and apoptosis in multiple HCC cell lines. Moreover, we observed that the enhancement of ABT-737-mediated apoptosis by NCTD was associated with activation of mitochondrial apoptosis signaling pathway, which involved cytosolic release of cytochrome c, cleavage of caspase-9 and caspase-3. Additionally, knockdown of Bax/Bak, the key effectors permeabilizing mitochondrial outer membrane significantly attenuated the enhancement, indicating mitochondrial apoptosis pathway played an essential role in the execution of the apoptosis. Finally, knockdown of Mcl-1 substantially potentiated ABT-737-mediated apoptotic cell death, confirming the potency of Mcl-1 repression by NCTD in enhancing ABT-737-induced apoptosis. These results therefore suggest that combination treatment with NCTD can overcome ABT-737 resistance and enhance ABT-737 therapeutic efficacy in treating human HCC.

Exploration of Chemical Space Based on 4-Anilinoquinazoline

Chemical space is defined as all possible small organic molecules, including those present in biological systems, which is so vast that so far only a tiny fraction of it has been explored. Indeed, a thorough examination of all "chemical space" is practically impossible. The success of three EGFR inhibitors (Gefitnib, Erlotinib, Lapatinib) suggests that 4-anilinoquinazoline scaffold is still worth developing in the future. To date hundreds of this sort of derivatives have been synthesized and show potent anticancer activities. Most of the compounds have been proved to be EGFR/HER2 kinase inhibitors, binding at the hinge region of the ATP site and some lead compounds have been optimized against a number of different kinases, including VEGFR-2, Src, Aurora A/B, Tpl, Clk and PDE10A. Now there is now a rich pipeline of novel anticancer agents based on 4-anilinoquinazoline in early phase clinical trials. This review will highlight the exploration of chemical space of 4-anilinoquinazoline in the past ten years and we hope that increasing knowledge of the SAR and cellular processes underlying the antitumor-activity of anilinoquinazoline derivatives will be beneficial to the rational design of new generation of small molecule anticancer drugs.

Strategies on the Development of Small Molecule Anticancer Drugs for Targeted Therapy

The main challenges currently encountered in chemotherapy are the lack of tumor selectivity and drug resistance. The design of novel cytostatic drugs has become the state-of-the-art technology in terms of targeted tumor therapy. This review illustrates the mechanisms and the advantages of representative chemotherapeutic agents, and presents an updated summary of the various drug design strategies developed by modern medicinal chemists during the most recent tumor targeting research which include rational design for overcoming drug resistance, the combi-targeting strategy, the prodrug approach, and tumor specific transporter based drug design. The concept of transporter related tumor targeting strategies for small molecule anticancer drug design discussed in this review may be amenable to predictable drug discovery for targeted therapy.

Next generation of antibody therapy for cancer

Monoclonal antibodies (mAbs) have become a major class of therapeutic agents providing effective alternatives to treating various human diseases. To date, 15 mAbs have been approved by regulatory agencies in the world for clinical use in oncology indications. The selectivity and specificity, the unique pharmacokinetics, and the ability to engage and activate the host immune system differentiate these biologics from traditional small molecule anticancer drugs. mAb-based regimens have brought clinical benefits, including improvements in overall survival, to patients with a variety of cancers. Many challenges still remain, however, to fully realize the potential of these new medicines. With our further understanding of cancer biology, mechanism of antibody action, and advancement of antibody engineering technologies, many novel antibody formats or antibody-derived molecules are emerging as promising new generation therapeutics. Carefully designed and engineered, they retain the advantage of specificity and selectivity of original antibodies, but in the meantime acquire additional special features such as improved pharmacokinetics, increased selectivity, and enhanced anticancer efficacy. Promising clinical results are being generated with these newly improved antibody-based therapeutics.

The Interactions of Anti-Cancer Drugs Approved in the Last Decade in the United States with Membrane Transporters

Membrane transporters play a role in determining the absorption, distribution, metabolism and excretion of small molecule anticancer drugs and mediating chemosensitivity and resistance of tumor cells to these drugs. Our understanding of the influence of these transporters on the pharmacokinetics, clinical effectiveness and tolerability has considerably increased in the last decade. Therefore, determining the interaction of membrane transporters with small molecule anticancer drugs can facilitate the development of effective and safe treatments. We reviewed the interaction of the small molecule anticancer drugs approved in the last decade with the more common membranes transporters, such as ABCB1, ABCG2, and OATP. The drugs were divided into three categories: targeted therapies, cytotoxic agents and hormonal therapies. The literature appears to focus on the interaction of the targeted therapies compared to the remaining two categories. Furthermore, most data stemmed from nonclinical studies with only a few clinical examples where transporters corresponded with systemic exposure or clinical effectiveness or tolerability. More nonclinical and clinical studies are needed to improve the ability to use the findings from these nonclinical studies to predict clinical outcomes, but the literature appears to be rapidly expanding as our understanding of these transporters groups. Therefore, determining the interaction of membrane transporters with small molecule anticancer drugs can be facilitate the development of effective and safe treatment.

Dynamics of telomeric chromatin at the crossroads of aging and cancer

Telomeres are nucleoprotein structures that protect the ends of human chromosomes through the formation of a 'cap', thus preventing exonucleolytic degradation, inter- and intra-chromosomal fusion, and subsequent chromosomal instability. During aging, telomere shortening correlates with tissue dysfunction and loss of renewal capacity. In human cancer, telomere dysfunction is involved in early chromosome instability, long-term cellular proliferation, and possibly other processes related to cell survival and microenvironment. Telomeres constitute an attractive target for the development of novel small-molecule anti-cancer drugs. In particular, individual protein components of the core telomere higher-order chromatin structure (known as the telosome or 'shelterin' complex) are promising candidate targets for cancer therapy.

Immunomodulatory drugs reorganize cytoskeleton by modulating Rho GTPases

AbstractIMiDs immunomodulatory drugs, including lenalidomide and pomalidomide represent a novel class of small molecule anticancer and anti-inflammatory drugs with broad biologic activities. However, the molecular mechanism through which these drugs exert their effects is largely undefined. Using pomalidomide and primary human monocytes, we report that pomalidomide rapidly and selectively activated RhoA and Rac1, but not Cdc42 or Ras, in the absence of any costimulation. Consistent with the activation of Rho GTPases, we found that pomalidomide enhanced F-actin formation, stabilized microtubules, and increased cell migration, all of which were blocked by selective inhibitors of ROCK1 and Rac1. Further, we showed that in Swiss 3T3 cells, pomalidomide only activated RhoA, not Rac1 or Cdc42, and potently induced stress fiber formation. The pomalidomide effect on actin cytoskeleton was blocked by the ROCK1 inhibitor, but not Rac1 inhibitor. Finally, we demonstrated that pomalidomide was able to regulate the activity of Rho GTPases and the formation of F-actin in primary human T cells as it did in monocytes and showed that the activation of RhoA was essential for pomalidomide-induced interleukin-2 expression in T cells. These novel activities provide what we believe a critical mechanism by which IMiDs drugs function as therapeutic immunomodulatory agents.