Treatment Of Drug-resistant Cancer Research Articles

Size-controlled, dual-ligand modified liposomes that target the tumor vasculature show promise for use in drug-resistant cancer therapy

Anti-angiogenic therapy is a potential chemotherapeutic strategy for the treatment of drug resistant cancers. However, a method for delivering such drugs to tumor endothelial cells remains to be a major impediment to the success of anti-angiogenesis therapy. We designed liposomes (LPs) with controlled diameter of around 300nm, and modified them with a specific ligand and a cell penetrating peptide (CPP) (a dual-ligand LP) for targeting CD13-expressing neovasculature in a renal cell carcinoma (RCC). We modified the LPs with an NGR motif peptide on the top of poly(ethylene glycol) and tetra-arginine (R4) on the surface of the liposome membrane as a specific and CPP ligand, respectively. The large size prevented extravasation of the dual-ligand LP, which allowed it to associate with target vasculature. While a single modification with either the specific or CPP ligand showed no increase in targetability, the dual-ligand enhanced the amount of delivered liposomes after systemic administration to OS-RC-2 xenograft mice. The anti-tumor activity of a dual-ligand LP encapsulating doxorubicin was evaluated and the results were compared with Doxil®, which is clinically used to target tumor cells. Even though Doxil showed no anti-tumor activity, the dual-ligand LP suppressed tumor growth because the disruption of tumor vessels was efficiently induced. The comparison showed that tumor endothelial cells (TECs) were more sensitive to doxorubicin by 2 orders than RCC tumor cells, and the disruption of tumor vessels was efficiently induced. Collectively, the dual-ligand LP is promising carrier for the treatment of drug resistant RCC via the disruption of TECs.

P2.13 Image-Guided and Targeted Therapy Using Theranostic Nanoparticles for Personalized Cancer Treatment

ABSTRACT Highly heterogeneous cancer cells represent the major challenge in clinical oncology for the treatment of human cancers. Novel therapeutic approaches that enable the application of personalized therapy for cancer patients hold great promise for effective treatment while minimizing systemic toxicity. We have developed an integrated cancer image-therapy protocol that takes advantages of multifunctionality of theranostic nanoparticles and advanced molecular imaging methods for biomarker-targeted tumor imaging and drug delivery, MRI monitoring therapeutic response, and optical image-guided surgery. Multifunctional magnetic iron oxide nanoparticles (IONPs) developed by our group are targeted to epidermal growth factor receptor, Her-2/Neu, and urokinase plasminogen activator receptor, which are biomarkers highly expressed in many types of human cancers. These receptor-targeted IONPs have capacity to carry single or multiple therapeutic agents for drug delivery, near infrared fluorescence and spectroscopic optical imaging, and magnetic resonance imaging (MRI). They are also designed to overcome physical and intrinsic barriers that reduce efficiency of drug delivery and confer drug resistance in human cancers. We have shown specificity and sensitivity of optical and MR imaging using the nanoparticles as targeted molecular contrast agents in orthotopic human breast, pancreatic, and ovarian cancer xenograft models. The development of biomarker targeted MRI nanoparticle probes should allow determining the level of biomarker expression in tumors using a non-invasive imaging approach for selection of the appropriate patients for targeted therapy. Based on the targeted imaging nanoparticles, we further developed methods to encapsulate or conjugate chemotherapy drugs into the nanoparticles. Efficacy of targeted therapy and MRI-monitoring drug delivery and response after systemic delivery of the theranostic nanoparticles has been demonstrated in orthotopic human breast, pancreatic and ovarian cancer xenograft models in nude mice. Since drug resistant residual tumors contain nanoparticles that produce optical signals, we applied hand-held optical imaging devices for detection and removal of drug resistant tumor lesions in the surgical cavity to prevent local recurrence and distant metastasis. The ultimate goal of our research is to translate this biomarker targeted therapy and image-guided treatment and surgery protocol into clinical applications for personalized management of cancer patients. Download : Download full-size image Fig. 1 . An integrated therapy-imaging approach for personalized therapy and effective treatment of drug-resistant cancers

Abstract 2896: Nanoparticle co-delivery of RNAi and chemotherapy for the treatment of drug-resistant cancers

Abstract The emergence of drug resistance has been a critical barrier for effective cancer chemotherapy. Recently, RNA interference (RNAi) has shown promise in suppressing the over-expression of drug resistance-associated proteins such as P-glycoprotein and Prohibitin1, and in treating multidrug resistant cancers through combination with chemotherapy. Nevertheless, the safe and effective delivery of RNAi therapeutics (e.g., siRNA and miRNA) to target cells remains a major hurdle for their clinical applications, and the co-delivery of RNAi and chemotherapeutic agents in a controlled fashion requires specific delivery vehicles. Herein, we present a novel nanoparticle (NP) platform to tackle the challenges associated with the delivery of siRNA and chemotherapeutic drugs, using biodegradable and biocompatible polymers and lipids. The hybrid lipid-polymer NP has a differentially charged hollow core/shell nanostructure which provides the delivery system with three distinct functional features: (i) a positively charged inner hollow core for dense loading of siRNA; (ii) a middle hydrophobic polymer layer for the encapsulation of anti-cancer drugs (e.g., taxanes) and for the controlled release of both siRNA and drug; and (iii) a relatively neutral lipid-polyethylene glycol (PEG) surface to keep the NP stable and prolong its systematic circulation. Moreover, such hybrid NPs can be formulated in a simple and robust way that could facilitate future scale-up. By screening various factors, such as inner cationic lipids, outer PEG chain length, and formulation parameters, the hybrid lipid-polymer NPs show excellent in vitro knockdown efficacy at low doses of siRNA, with greater than 80% luciferase silencing at an siRNA dose of 0.4 pmol (4.0 nM) and ∼ 95% silencing at a dose of 2.0 pmol (20 nM). These NPs can also efficiently reduce the expression of drug resistance-associated proteins (e.g., MDR1 and Prohibitin1), as evidenced by qPCR. Cellular cytotoxicity experiments further confirm that this NP co-delivery strategy can drastically improve the sensitivity of drug-resistant cells to chemotherapy. In addition, these hybrid NPs demonstrate promising in vivo results for co-delivering siRNA and chemotherapeutic drugs to treat drug-resistant cancers. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2896. doi:1538-7445.AM2012-2896

Structure–Activity Relationship and Molecular Mechanisms of Ethyl 2-Amino-6-(3,5-dimethoxyphenyl)-4-(2-ethoxy-2-oxoethyl)-4H-chromene-3-carboxylate (CXL017) and Its Analogues

Multidrug resistance (MDR) in cancer is a phenomenon in which administration of a single chemotherapeutic agent causes cross-resistance of cancer cells to a variety of therapies even with different mechanisms of action. Development of MDR against standard therapies is a major challenge in the treatment of cancer. Previously we have demonstrated a unique ability of CXL017 (5) to selectively target MDR cancer cells and synergize with mitoxantrone (MX) in HL60/MX2 MDR cells. Here we expand its scope and demonstrate that 5 can synergize with both vincristine and paclitaxel in three different MDR cell lines (HL60/DNR, K562/HHT300, and CCRF-CEM/VLB100). We also demonstrate that 5 has potent cytotoxicity in the NCI-60 panel of cell lines with an average IC(50) of 1.04 μM. In addition, 5 has a unique mechanism of action in comparison with standard agents in the NCI database based on COMPARE analysis. Further structure-activity relationship study led to the development of a more potent analogue, compound 7d, with an IC(50) of 640 nM in HL60/MX2. Additionally, one enantiomer of 5 is 13-fold more active than the less active enantiomer. Taken together, our study has led to the discovery of a series of analogues that selectively target drug-resistant cancer cells with the potential for the treatment of drug-resistant cancers.

Abstract 739: Small molecule inhibitor, PZ39C8, promotes BCRP degradation via binding to TM5-loop-TM6

Abstract Multidrug resistance (MDR) and existing cancer stem cells (CSCs) are two major problems in successful treatment of cancers. Expression of breast cancer resistance protein (BCRP) is known to associate with both MDR and CSCs, suggesting that BCRP is an interesting and ideal target for development of chemosensitizing agents for better treatment of drug resistant cancers and elimination of CSCs. Recently, we identified a novel BCRP inhibitor PZ39 and its analogue compound PZ39C8 which are capable of inhibiting BCRP function and inducing BCRP degradation in lysosome. In the present study, we (1) investigated the mechanism of inhibitor-induced BCRP degradation using a stable cell line expressing GFP-BCRP in combination with pharmacological agents of endocytosis and trafficking and (2) determined the inhibitor binding site in BCRP using compound-conjugated Sepharose 4B beads and pull-down assay. We found that (1) the lysosomal inhibitor Bafilomycin A but not the proteosome inhibitor MG132 abolished PZ39C8-induced BCRP degradation; (2) dynasore, a potent endocytosis inhibitor, and 3-Methyladenine, a autophagy inhibitor, both efficiently blocked the PZ39C8-induced BCRP degradation from plasma and internal membranes; (3) following co-treatment with PZ-39C8 and endocytosis, trafficking, and lysosome inhibitors, BCRP co-localized with the LAMP-1, LC3II and Clathrin, EEA1, the markers of Lysosome, autophagy and endocytic pathways, respectively; and (4) PZ39C8 directly binds BCRP and the binding site/s appears to locate in the domain including TM5-loop-TM6. Taken together, we conclude that PZ39C8 binds to TM5-ECL3-TM6 of BCRP and induces BCRP degradation in lysosome via endocytic and autophagic dependent pathways. Thus, PZ39C8 is potentially a valuable probe for structure-function studies of BCRP and a lead compound for developing therapeutics targeting BCRP-mediated MDR in combinational cancer chemotherapy. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 739. doi:10.1158/1538-7445.AM2011-739

Dynamic vs Static ABCG2 Inhibitors to Sensitize Drug Resistant Cancer Cells

Human ABCG2, a member of the ATP-binding cassette transporter superfamily, plays a key role in multidrug resistance and protecting cancer stem cells. ABCG2-knockout had no apparent adverse effect on the development, biochemistry, and life of mice. Thus, ABCG2 is an interesting and promising target for development of chemo-sensitizing agents for better treatment of drug resistant cancers and for eliminating cancer stem cells. Previously, we reported a novel two mode-acting ABCG2 inhibitor, PZ-39, that induces ABCG2 degradation in addition to inhibiting its activity. In this manuscript, we report our recent progresses in identifying two different groups of ABCG2 inhibitors with one inhibiting only ABCG2 function (static) and the other induces ABCG2 degradation in lysosome in addition to inhibiting its function (dynamic). Thus, the inhibitor-induced ABCG2 degradation may be more common than we previously anticipated and further investigation of the dynamic inhibitors that induce ABCG2 degradation may provide a more effective way of sensitizing ABCG2-mediated MDR in cancer chemotherapy.

Expression of P-glycoprotein in HeLa cells confers resistance to ceramide cytotoxicity

The role of glucosylceramide synthase (GCS) in regulating ceramide-induced apoptosis has been widely studied. The purpose of this investigation was to evaluate the role of P-glycoprotein (P-gp) in regulating ceramide cytotoxicity by using C6-ceramide. To accomplish this, we employed HeLa cells with conditional expression of the multidrug resistance gene 1/P-gp. HeLa cells expressing P-gp (P-gp/on cells) challenged with [14C]C6-ceramide (6 µM), synthesized 4.5-fold the amount of C6-glucosylceramide (GC) compared to HeLa cells with suppressed expression of P-gp (P-gp/off cells), whereas the generated levels of C6-sphingomyelin were almost equal (33 and 29% of intracellular 14C, respectively). Tamoxifen, a P-gp antagonist, decreased the C6-GC levels from 3.5-1.0% in the P-gp/off and from 17-2.8% of the total lipid 14C levels in the P-gp/on cells. Tamoxifen did not inhibit cell-free C6-GC synthesis in the P-gp/off or P-gp/on homogenates. However, a specific GCS inhibitor, ethylenedioxy-1-phenyl-2-hexadecanoylamino-3-pyrrolidino-1-propanol (ethylenedioxy-P4), blocked synthesis by 90%. In the cytotoxicity assays, the P-gp/off cells were sensitive to C6-ceramide and the P-gp/on cells were resistant. Resistance to C6-ceramide in the P-gp/on cells was reversed by tamoxifen but not by ethylenedioxy-P4. Experiments in another cervical cancer model showed that multidrug-resistant P-gp-rich KB-V1 cells synthesized 3-fold more C6-GC from C6-ceramide than the parental, P-gp-poor KB-3-1 cells, and whereas tamoxifen had no effect on the C6-GC synthesis in the KB-3-1 cells, it inhibited synthesis by 70% in the KB-V1 cells. This study demonstrates that P-gp potentiates C6-ceramide glycosylation and if antagonized augments C6-ceramide sensitivity, both features previously ascribed to GCS. We propose that P-gp can be an effective target for enhancing short-chain ceramide cytotoxicity in the treatment of drug-resistant cancer.

Rescue of paclitaxel sensitivity by repression of Prohibitin1 in drug-resistant cancer cells

Paclitaxel has emerged as a front line treatment for aggressive malignancies of the breast, lung, and ovary. Successful therapy of cancer is frequently undermined by the development of paclitaxel resistance. There is a growing need to find other therapeutic targets to facilitate treatment of drug-resistant cancers. Using a proteomics approach, elevated levels of Prohibitin1 (PHB1) and GSTpi were found associated with paclitaxel resistance in discrete subcellular fractions of two drug-resistant sublines relative to their sensitive sublines. Immunofluorescence staining and fractionation studies revealed increased levels of PHB1 on the surface of resistant cell lines. Transiently silencing either PHB1 or GSTpi gene expression using siRNA in the paclitaxel-resistant cancer cell sublines partially sensitized these cells toward paclitaxel. Intriguingly, silencing PHB1 but not GSTpi resulted in activation of the intrinsic apoptosis pathway in response to paclitaxel. Similarly, stably silencing either PHB1 or GSTpi significantly improved paclitaxel sensitivity in A549TR cells both in vitro and in vivo. Our results indicate that PHB1 is a mediator of paclitaxel resistance and that this resistance may depend on the cellular localization of the protein. We suggest PHB1 as a potential target for therapeutic strategies for the treatment of drug-resistant tumors.

A Novel Two Mode-Acting Inhibitor of ABCG2-Mediated Multidrug Transport and Resistance in Cancer Chemotherapy

BackgroundMultidrug resistance (MDR) is a major problem in successful treatment of cancers. Human ABCG2, a member of the ATP-binding cassette transporter superfamily, plays a key role in MDR and an important role in protecting cancer stem cells. Knockout of ABCG2 had no apparent adverse effect on the mice. Thus, ABCG2 is an ideal target for development of chemo-sensitizing agents for better treatment of drug resistant cancers and helping eradicate cancer stem cells.Methods/Preliminary FindingsUsing rational screening of representatives from a chemical compound library, we found a novel inhibitor of ABCG2, PZ-39 (N-(4-chlorophenyl)-2-[(6-{[4,6-di(4-morpholinyl)-1,3,5-triazin-2-yl]amino}-1,3-benzothiazol-2-yl)sulfanyl]acetamide), that has two modes of actions by inhibiting ABCG2 activity and by accelerating its lysosome-dependent degradation. PZ-39 has no effect on ABCB1 and ABCC1-mediated drug efflux, resistance, and their expression, indicating that it may be specific to ABCG2. Analyses of its analogue compounds showed that the pharmacophore of PZ-39 is benzothiazole linked to a triazine ring backbone.Conclusion/SignificanceUnlike any previously known ABCG2 transporter inhibitors, PZ-39 has a novel two-mode action by inhibiting ABCG2 activity, an acute effect, and by accelerating lysosome-dependent degradation, a chronic effect. PZ-39 is potentially a valuable probe for structure-function studies of ABCG2 and a lead compound for developing therapeutics targeting ABCG2-mediated MDR in combinational cancer chemotherapy.

Reversion of multidrug resistance by co-encapsulation of vincristine and verapamil in PLGA nanoparticles

Multidrug resistant (MDR) cancer may be treated using combinations of encapsulated cytotoxic drugs and chemosensitizers. To optimize the effectiveness of this combinational approach, poly( d, l-lactide-co-glycolide acid) (PLGA) nanoparticles formulations capable of delivering a cytotoxic drug, vincristine, a chemosensitizer, verapamil, or their combination were prepared via combining O/W emulsion solvent evaporation and salting-out method. Moreover, this work evaluated a number of approaches for the administration of chemosensitizer-cytotoxic drug combinations in a systematic fashion. The results showed that the administration sequence of anticancer drug and chemosensitizer was critical for maximal therapeutic efficacy and the simultaneous administration of vincristine and verapamil could achieve the highest reversal efficacy. In addition, PLGA nanoparticles (PLGANPs) showed moderate MDR reversal activity on MCF-7/ADR cells resistant to vincristine. The dual-agent loaded PLGA nanoparticles system resulted in the similar cytotoxicity to one free drug/another agent loaded PLGANPs combination and co-administration of two single-agent loaded PLGANPs, which was slightly higher than that of the free vincristine/verapamil combination. Co-encapsulation of anticancer drug and chemosensitizer might cause lower normal tissue drug toxicity and fewer drug–drug interactions. Therefore, we speculate that PLGANPs simultaneously loaded with anticancer drug and chemosensitizer might be the most potential formulation in the treatment of drug resistant cancers in vivo.

Advances of clinical treatment of drug-resistant advanced breast cancer

In the current clinical trials,observed treatment on recrudescent and metastatic breast cancer which can be anthracycline-resistant and taxane-resistant with Ixabepilone、Larotaxel and their combination;and treating climacteric-positive and tamoxifen-resistant advanced breast cancer with steroid sulfatase inhibitor STX64 or combination of exemestane and celecoxib;Treating chemotherapy-refractory HER2-positive metastatic breast cancer with lapatinib and pemetrexed as well as their combination.Results have demonstrated superior efficacy and safety,and some of which are worthy of further observation. Key words: Breast neoplasms; Drug therapy

SHA 14-1, a stable and ROS-free antagonist against anti-apoptotic Bcl-2 proteins, bypasses drug resistances and synergizes cancer therapies in human leukemia cell

HA 14-1, a small-molecule antagonist against anti-apoptotic Bcl-2 proteins, was demonstrated to induce selective cytotoxicity toward malignant cells and to overcome drug resistance. Due to its poor stability and the reactive oxygen species (ROS) generated by its decomposition, chemical modification of HA 14-1 is needed for its future development. We have synthesized a stabilized analog of HA 14-1 – sHA 14-1, which did not induce the formation of ROS. As expected from a putative antagonist against anti-apoptotic Bcl-2 proteins like HA 14-1, sHA 14-1 disrupted the binding interaction of a Bak BH3 peptide with Bcl-2 or Bcl-X L protein, inhibited the growth of tumor cells through the induction of apoptosis, and circumvented the drug resistance induced by the over-expression of anti-apoptotic Bcl-2 and Bcl-X L proteins. Interestingly, the impairment of extrinsic apoptotic pathway induced moderate resistance to sHA 14-1. The moderate resistance suggested that sHA 14-1 generated part of its apoptotic stress through the intrinsic pathway, possibly through its antagonism against anti-apoptotic Bcl-2 proteins. The resistance indicated that sHA 14-1 generated apoptotic stress through the extrinsic apoptotic pathway as well. The ability of sHA 14-1 to induce apoptotic stress through both pathways was further supported by the synergism of sHA 14-1 towards the cytotoxicities of Fas ligand and dexamethasone in Jurkat cells. Taken together, these findings suggest that sHA 14-1 may represent a promising candidate for the treatment of drug-resistant cancers either as a monotherapy or in combination with current cancer therapies.

Tumor Therapy Mediated by Lentiviral Expression of shBcl-2 and S-TRAIL

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) can selectively kill tumor cells and, in combination with other agents, could enhance tumor therapy. We explored the combined therapeutic effects of a secretable form of (S) TRAIL-induced apoptosis and the downregulation of Bcl-2 in human gliomas. We constructed a lentiviral delivery system: 1) for the expression of short hairpin (sh) RNA to downregulate Bcl-2 and for the expression of S-TRAIL to induce apoptosis in glioma cells; and 2) to follow delivery in vitro and the fate of tumors in real time in vivo. We demonstrate that lentiviral-mediated simultaneous downregulation of Bcl-2 and S-TRAIL-induced apoptosis leads to an increased expression of activated caspase-3 and caspase-7, thus resulting in accelerated S-TRAIL-mediated apoptosis in glioma cells in vitro. Using a highly malignant human glioma model expressing EGFRvIll and firefly luciferase, we show that the combined effect of Bcl-2 downregulation and S-TRAIL-induced apoptosis results in complete eradication of gliomas compared to S-TRAIL monotherapy. These results show that simultaneous triggering of TRAIL-mediated death receptor pathway and downregulation of Bcl-2 by shRNA leads to enhanced eradication of gliomas and serves as a template in developing and monitoring combination therapies for the treatment of drug-resistant cancers.

2-Methoxyestradiol alters cell motility, migration, and adhesion

AbstractThe effect of 2-methoxyestradiol, 2ME2, an endogenous metabolite of 17β-estradiol (E2), on cell growth and cytoskeletal functions in a BCR-ABL—transformed cell line model was investigated. We determined the interaction of 2ME2 with STI571 (Gleevec, imatinib mesylate) in STI571 drug-sensitive and -resistant cell lines. In cells expressing BCR-ABL, STI571 cooperated with 2ME2 in reducing cell growth, and STI571-resistant cells were sensitive to 2ME2 treatment. 2ME2 also inhibited growth of several cancer cell lines by a mechanism independent of BCR-ABL. BCR-ABL transformation leads to altered motility, increased adhesion, and spontaneous migration in different in vitro model systems. 2ME2 was found to specifically inhibit the spontaneous motility of BCRABL—transformed Ba/F3 cells and to change the morphology and volume of treated cells. Cells attached to fibronectin-coated surfaces showed a reduced number of filipodia and lamellipodia. In addition, 2ME2 significantly reduced BCRABL—mediated adhesion to fibronectin. The spontaneous migration of BCR-ABL—transformed cells through a transwell membrane also was found to be significantly decreased by 2ME2. Cytoskeletal changes were accompanied by alteration of tubulin formation, distinct from paclitaxel treatment. These results demonstrate that 2ME2 treatment of transformed cells strongly reduces cytoskeletal functions and may also be useful for the treatment of cancers with high metastatic potential. Combination of 2ME2 with other anticancer drugs may be beneficial to treatment of drug-resistant cancers. (Blood. 2003;102:289-296)

Enhanced oncolytic potency of replicative adenovirus expressing p53.

One emerging approach to improve the treatment of drug-resistant cancers involves targeting of therapeutic genes by adenoviral delivery to tumor cells. Resistance to cytotoxic agents commonly occurs because the cytotoxic is an external agent that depends upon cellular exposure to achieve its affects. Decreases in uptake or retention by the cancer cell result in suboptimal exposure and reduced effect. Recent understanding of basic cellular processes in normal cells and how they go awry in cancer has yielded new therapeutic opportunities using viral delivery vehicles to target the cancer specific abnormalities (Borst et al., 2001; Nemunaitis and Cunningham, 2002). Persistent investigation into the mechanism(s) of selective replication and associated oncolytic effect of DNA viruses in malignant tissue continues to yield fruitful results. Three replicative DNA viral constructs: adenovirus (Khuri et al., 2000; Nemunaitis et al., 2001b), herpes simples virus (Kucharzuk et al., 1997; Toyozuimi et al., 1999) and vaccinia virus (Gomella et al., 2001; Mastrangelo et al., 2000) are currently being explored clinically. Each of these viruses has demonstrated reasonable tolerability and evidence of activity when administered via local regional approaches, however, none have shown systemic activity. Our own experience with ONYX-015 (an E1b deleted selective replicating adenovirus) illustrates this point. Despite significant clinical activity with intratumoral injection of ONYX 015 (Khuri et al., 2000; Nemunaitis et al., 2001b), intravenous infusion produced no clinical responses despite clear evidence of viral access to malignant tissue. Electron micrographs of tumor obtained from treated patients showed clumps of intranuclear viral particles within malignant tissue, but there was little or no evidence of oncolysis (Nemunaitis et al., 2001a, in press). We theorized that this lack of activity might be due to low concentrations of viral particles actually presenting to malignant tissue because of hepatic

Drug resistance does not correlate with resistance to Fas-mediated apoptosis

Recent reports have correlated multidrug resistance (MDR) and P-glycoprotein expression with decreased Fas expression and resistance to Fas-mediated apoptosis. We report the MRP-overexpressing MDR subline CEM/E1000 has the same Fas expression (MFI 74.3±0.7) as the parental CCRF-CEM T-cell leukaemia cells (MFI 70.0±3.6; P>0.05), and that the level of apoptosis induced by anti-Fas antibody or drug was similar in both cell lines. Further the P-glycoprotein-expressing CEM/VLB 100 subline of the CCRF-CEM cells showed increased Fas expression (MFI 114.8±3.6; P<0.001) and no resistance to Fas-mediated apoptosis. This questions the hypothesis that selection of drug resistance results in resistance to Fas-mediated apoptosis, with important implications for the rational use of immunotherapy in the treatment of drug resistant cancer.

Sigma receptors: recent advances and new clinical potentials

Several recent advances are leading to a better understanding of sigma receptors. Here we focus on our recent findings regarding cellular functions of sigma-2 receptors and discuss their possible clinical implications. Agonists at sigma-2 receptors induced changes in cell morphology and apoptosis in various cell types. Sigma-2 receptor activation produced both transient and sustained increases in [Ca++]i, derived from different intracellular stores. These changes in [Ca++]i and cytotoxic effects are mediated by intracellular sigma-2 receptors. Sigma-2 agonists induced apoptosis in drug-resistant cancer cells, enhanced the potency of DNA damaging agents, and down-regulated expression of p-glycoprotein mRNA. Thus, sigma-2 receptor agonists may be useful in treatment of drug-resistant cancers. Sigma radioligands have been used in tumor imaging. We also discuss how sigma-2 antagonists might prevent the irreversible motor side effects of typical neuroleptics. Sigma-2 receptors may subserve a novel signalling pathway to apoptosis, involved in regulation of cell proliferation and/or viability.

Nitric oxide donors: Novel cancer therapeutics (Review)

The development of cancer cell resistance to various cytotoxic stimuli continues to be a major challenge in oncology and novel therapeutic approaches are urgently needed. Nitric oxide (NO) is emerging as a potential anti-oncogenic agent to overcome tumor cell resistance to conventional therapeutic agents. NO is a ubiquitous, water-soluble, free radical gas that exerts a wide range of biological effects. The actions of nitric oxide are highly variable in oncology with reports in the literature on both sides of the spectrum as an anti-neoplastic vs. a pro-neoplastic agent. The final activity of NO in oncology is dependent on its working microenvironment, including the type of cell exposed to the compound, the redox state of the reaction, as well as the final intracellular concentration and the duration of intracellular exposure to nitric oxide. There is, however, no unifying mechanistic explanation for the biphasic role of nitric oxide in oncology. Nitric oxide donors mimic continuous production of NO in a wide range of time intervals (seconds to days). Thus, multiple biological and (pro- vs. anti-) neoplastic responses are elicited from NO donors depending on the half-life and the type of cell exposed to the compound. The large variety of nitric oxide donors may serve as a tool to explore the wide range of oncologic properties of NO in cancer. In the present report, we discuss classic nitric oxide donors and their potential therapeutic roles as cytotoxic agents or chemo-radio or -immune-sensitizing compounds in the treatment of drug-resistant cancers.