Natural Taxanes: From Plant Composition to Human Pharmacology and Toxicity.

Biologically active taxanes, present in small- to medium-sized evergreen conifers of various Taxus species, are widely used for their antioxidant, antimicrobial and anti-inflammatory effects, but mostly for their antitumour effects used in the treatment of solid tumours of the breast, ovary, lung, bladder, prostate, oesophagus and melanoma. More of the substances found in Taxus plant extracts have medical potential. Therefore, at the beginning of this review, we describe the methods of isolation, identification and determination of taxanes in different plant parts. One of the most important taxanes is paclitaxel, for which we summarize the pharmacokinetic parameters of its different formulations. We also describe toxicological risks during clinical therapy such as hypersensitivity, neurotoxicity, gastrointestinal, cardiovascular, haematological, skin and renal toxicity and toxicity to the respiratory system. Since the effect of the drug-form PTX is enhanced by various Taxus spp. extracts, we summarize published clinical intoxications and all fatal poisonings for the Taxus baccata plant. This showed that, despite their significant use in anticancer treatment, attention should also be focused on the risk of fatal intoxication due to ingestion of extracts from these plants, which are commonly found in our surroundings.

Brevifoliol and its Analogs: A New Class of Anti-tubercular Agents.

Brevifoliol is an abeo-taxane isolated from the Taxus wallichiana needles; eighteen semisynthetic esters derivatives of brevifoliol were prepared by Steglich esterification and screened for their anti-tubercular potential against Mycobacterium tuberculosis H37Ra avirulent strain. The 3- [chloro (7)] and 3, 5-[dinitro (8)] benzoic acid ester derivatives were most active (MIC 25 ug/ml) against the pathogen. Further, in silico docking studies of the active derivative 7 with mycobacterium enzyme inhA (enoyl-ACP reductase) gave the LibDock score of 152.68 and binding energy of -208.62 and formed three hydrogen bonds with SER94, MET98, and SER94. Similarly, when derivative 8 docked with inhA, it gave the LibDock score of 113.55 and binding energy of -175.46 and formed a single hydrogen bond with GLN100 and Pi-interaction with PHE97. On the other hand, the known standard drug isoniazid (INH) gave the LibDock score of 61.63, binding energy of -81.25 and formed one hydrogen bond with ASP148. These molecular docking results and the way of binding pattern indicated that compounds 7 and 8 bound well within the binding pocket of inhA and showed a higher binding affinity than the known drug isoniazid. Additionally, both the derivatives (7 and 8) showed no cytotoxicity, with CC50 195.10 and 111.36, respectively towards the mouse bone marrow-derived macrophages.

Pathological and Pharmacological Roles of Mitochondrial Reactive Oxygen Species in Malignant Neoplasms: Therapies Involving Chemical Compounds, Natural Products, and Photosensitizers.

Oxidative stress plays an important role in cellular processes. Consequently, oxidative stress also affects etiology, progression, and response to therapeutics in various pathological conditions including malignant tumors. Oxidative stress and associated outcomes are often brought about by excessive generation of reactive oxygen species (ROS). Accumulation of ROS occurs due to dysregulation of homeostasis in an otherwise strictly controlled physiological condition. In fact, intracellular ROS levels are closely associated with the pathological status and outcome of numerous diseases. Notably, mitochondria are recognized as the critical regulator and primary source of ROS. Damage to mitochondria increases mitochondrial ROS (mROS) production, which leads to an increased level of total intracellular ROS. However, intracellular ROS level may not always reflect mROS levels, as ROS is not only produced by mitochondria but also by other organelles such as endoplasmic reticulum and peroxisomes. Thus, an evaluation of mROS would help us to recognize the biological and pathological characteristics and predictive markers of malignant tumors and develop efficient treatment strategies. In this review, we describe the pathological significance of mROS in malignant neoplasms. In particular, we show the association of mROS-related signaling in the molecular mechanisms of chemically synthesized and natural chemotherapeutic agents and photodynamic therapy.

Brevifoliol ester induces apoptosis in prostate cancer cells by activation of caspase pathway.

Prostate cancer is fourth most abundant cancer type around the globe. Brevifoliol, a rearranged taxoid from Taxus walllichiana needles has been derivatized as C5 esters using Steglich esterification reaction. Seventeen diverse analogues were evaluated against a panel of human cancer cell lines by MTT assay. Among these, two of the semi-synthetic analogues, that is, 13 and 16 exhibited potent cytotoxicity, selectively against PC-3, prostate cancer cell lines. In cell cycle analysis, analogue 13 induced S and G2/M phase arrest and induced apoptosis by activating caspase-3. Compound 13 showed moderate efficacy in in-vivo Ehrlich ascites carcinoma in Swiss albino mice. Further, compound 13 was found to be safe in Swiss albino mice up to 1,000 mg/kg dose in acute oral toxicity. Brevifoliol ester 13 may further be optimized for better efficacy.

Effects of Black Raspberries and Their Ellagic Acid and Anthocyanin Constituents on Taxane Chemotherapy of Castration-Resistant Prostate Cancer Cells.

Cancer patients often use dietary supplements while on therapy, but little is known about interactions of supplements with cancer chemotherapy. Black raspberries (BRB) have anti-cancer effects, but have not been evaluated for interference with chemotherapy for castrate-resistant prostate cancer (CRPC). Here we studied whether BRB and some of their constituents interact with docetaxel and cabazitaxel on CRPC cells in culture and implanted into nude mice. Ellagic acid increased, but BRB extract inhibited, microtubule assembly. Ellagic acid decreased tubulin polymerization by cabazitaxel and bound to tubulin. Ellagic acid, its metabolite urolithin A, BRB extract, and the anthocyanin metabolite protocatechuic acid (PCA) did not alter cytotoxicity of taxanes. Ellagic acid inhibited drug efflux in CRPC cells, but BRB extract and PCA did not. None of these compounds altered CYP3A4 activity. Although dietary ellagic acid did not alter the tumor growth inhibition by docetaxel of xenografted 22Rv1 cells, ellagic acid has the potential to interfere with taxane chemotherapy by reducing tubulin polymerization while inhibiting P-glycoprotein drug efflux. These data are cause for concern of consuming ellagic acid during treatment for CRPC and indicate need for further research, but BRB consumption appears safe.

Lack of combination effects of soy isoflavones and taxane chemotherapy of castration-resistant prostate cancer.

BACKGROUND: Patients with cancer, including prostate cancer, often use dietary supplements, such as soy or isoflavones, before, during, or after therapy. There is little information about possible interactions between supplements and cancer chemotherapy. There are some reports suggesting enhancement by genistein of taxane chemotherapy for castrate-resistant prostate cancer (CRPC). METHODS: We investigated whether physiologically attainable concentrations of soy isoflavones (≤10 µM) interact with taxanes on growth inhibition of CRPC cells in vitro and in vivo in nude mice exposed via the diet, on microtubule disassembly in vitro, and on P-glycoprotein-mediated drug efflux in 22Rv1 cells and CYP3A4 activity in microsomes. RESULTS: Genistein, daidzein, and equol did not affect growth of VCaP, 22Rv1, C4-2, and PC-3 CRPC cells or growth inhibition of these cells by docetaxel and cabazitaxel. These isoflavones did not inhibit microtubule disassembly in vitro or inhibit the microtubule effects of taxanes and genistein did not bind substantially to microtubules. Genistein considerably inhibited P-glycoprotein-mediated drug efflux in 22Rv1 cells and CYP3A4 activity in microsomes. However, dietary supplementation with genistein at 250 and 500 ppm did not affect the tumor growth inhibiting effect of docetaxel on 22Rv1 cells xenografted in nude mice. CONCLUSIONS: Our results with relevant cell models and clinically achievable concentrations of soy isoflavones do not support the notion that genistein or other soy isoflavones can enhance the effects of taxane chemotherapy in CRPC cell and xenograft models. Yet, the inhibitory effects of genistein on drug efflux in 22Rv1 cells and on microsomal CYP3A4 activity raise the possibility that genistein can affect taxane effects on CRPC cells in other circumstances than those we studied, which merits further research.

Suppression of Taxanes Cytotoxicity by Citrus Flavonoid Hesperetin in PPC-1 Human Prostate Cancer Cells.

BACKGROUND/AIM: More than half of prostate cancer patients use, in addition to conventional therapies, some kind of complementary medicine, including flavonoid-rich products. However, knowledge about the co-effects of flavonoids with cytotoxic chemotherapies is still rather poor. Therefore, this study was undertaken to assess the cytotoxic activity of flavonoids and their interactions with taxanes in human advanced prostate cancer cells. MATERIALS AND METHODS: Cytotoxicity of different flavonoids and their effects on the efficacy of docetaxel and cabazitaxel were studied in the human metastatic prostate cancer cell line PPC-1, using MTT colorimetric assay. RESULTS: Both taxanes suppressed the viability of PPC-1 cells with IC50 values in the nanomolar range. Tested flavonoids exerted cytotoxic activity only at high micromolar concentrations or revealed no remarkable effect on cell survival. Simultaneous treatment of cells with taxanes and flavonoids baicalein, chrysin, luteolin, fisetin, quercetin, genistein or daidzein did not lead to any change in chemotherapy-induced cytotoxicity. However, simultaneous exposure of cells to hesperetin and taxanes resulted in 9.8- and 13.1-fold reduction in cytotoxicity of docetaxel and cabazitaxel, respectively. CONCLUSION: Flavonoid hesperetin remarkably suppressed the cytotoxic efficacy of taxanes in prostate cancer cells. Therefore, caution is required from prostate cancer patients who take hesperetin-containing oral supplements.

CCL20 triggered by chemotherapy hinders the therapeutic efficacy of breast cancer.

Chemotherapeutic resistance in triple-negative breast cancer (TNBC) has brought great challenges to the improvement of patient survival. The mechanisms of taxane chemoresistance in TNBC have not been well investigated. Our results illustrated C-C motif chemokine ligand 20 (CCL20) was significantly elevated during taxane-containing chemotherapy in breast cancer patients with nonpathologic complete response. Furthermore, CCL20 promoted the self-renewal and maintenance of breast cancer stem cells (BCSCs) or breast cancer stem-like cells through protein kinase Cζ (PKCζ) or p38 mitogen-activated protein kinase (MAPK)-mediated activation of p65 nuclear factor kappa B (NF-κB) pathway, significantly increasing the frequency and taxane resistance of BCSCs. Moreover, CCL20-promoted NF-κB activation increased ATP-binding cassette subfamily B member 1 (ABCB1)/multidrug resistance 1 (MDR1) expression, leading to the extracellular efflux of taxane. These results suggested that chemotherapy-induced CCL20 mediated chemoresistance via up-regulating ABCB1. In addition, NF-κB activation increased CCL20 expression, forming a positive feedback loop between NF-κB and CCL20 pathways, which provides sustained impetus for chemoresistance in breast cancer cells. Our results suggest that CCL20 can be a novel predictive marker for taxane response, and the blockade of CCL20 or its downstream pathway might reverse the taxane resistance in breast cancer patients.

Bispecific antibodies (anti-mPEG/anti-HER2) for active tumor targeting of docetaxel (DTX)-loaded mPEGylated nanocarriers to enhance the chemotherapeutic efficacy of HER2-overexpressing tumors.

Anti-mPEG/anti-human epidermal growth factor receptor 2 (HER2) bispecific antibodies (BsAbs) non-covalently bound to a docetaxel (DTX)-loaded mPEGylated lecithin-stabilized micellar drug delivery system (LsbMDDs) were endowed with active targetability to improve the chemotherapeutic efficacy of DTX. DTX-loaded mPEGylated LsbMDDs formulations were prepared using lecithin/DSPE-PEG(2K or 5K) nanosuspensions to hydrate the thin film, and then they were subjected to ultrasonication. Two BsAbs (anti-mPEG/anti-DNS or anti-HER2) were simply mixed with the LsbMDDs to form BsAbs-LsbMDDs formulations, respectively, referred as the DNS-LsbMDDs and HER2-LsbMDDs. Results demonstrated that the physical characteristics of the BsAbs-LsbMDDs were similar to those of the plain LsbMDDs but more slowly released DTX than that from the LsbMDDs. Results also showed that the HER2-LsbMDDs suppressed the growth of HER2-expressing MCF-7/HER2 tumors, increasing the amount taken up via an endocytosis pathway leading to high drug accumulation and longer retention in the tumor. In conclusion, the BsAbs-LsbMDDs preserved the physical properties of the LsbMDDs and actively targeted tumors with a drug cargo to enhance drug accumulation in tumors leading to greater antitumor activity against antigen-positive tumors.

Carotenoid Lutein Selectively Inhibits Breast Cancer Cell Growth and Potentiates the Effect of Chemotherapeutic Agents through ROS-Mediated Mechanisms.

Increasing evidence suggests that dietary carotenoids may reduce the risk of breast cancer. However, anti-breast cancer effects of carotenoids have been controversial, albeit understudied. Here, we investigated the effects of specific carotenoids on a wide range of breast cancer cell lines, and found that among several carotenoids (including ß-carotene, lutein, and astaxanthin), lutein significantly inhibits breast cancer cell growth by inducing cell-cycle arrest and caspase-independent cell death, but it has little effect on the growth of primary mammary epithelial cells (PmECs). Moreover, lutein-mediated growth inhibition of breast cancer cells is quantitatively similar to that induced by chemotherapeutic taxanes, paclitaxel and docetaxel, and exposure to lutein plus taxanes additively inhibits breast cancer cell growth. Analysis of mechanisms showed that lutein treatment significantly increases the intracellular reactive oxygen species (ROS) production in triple-negative breast cancer (TNBC) cells, but not in normal PmECs. Lutein-induced growth inhibition is also attenuated by the radical oxygen scavenger N-acetyl cysteine, suggesting a role for ROS generation in the growth inhibitory effect of lutein on TNBC cells. Additionally, we found that the p53 signaling pathway is activated and HSP60 levels are increased by lutein treatment, which may contribute partly to the induction of growth inhibition in TNBC cells. Our findings show that lutein promotes growth inhibition of breast cancer cells through increased cell type-specific ROS generation and alternation of several signaling pathways. Dietary lutein supplementation may be a promising alternative and/or adjunct therapeutic candidate against breast cancer.

Dual tumor-targeted multifunctional magnetic hyaluronic acid micelles for enhanced MR imaging and combined photothermal-chemotherapy.

Multifunctional polymeric micelles were developed as a promising dual tumor-targeted drug delivery platform for magnetic resonance (MR) imaging and combined photothermal-chemotherapy. HA-C16 copolymers were synthesized via peptide formation process with subsequent co-encapsulation of therapeutic agent docetaxel (DTX) and superparamagnetic iron oxide nanoparticles (SPIONs) to form the multifunctional micelles. The micelles exhibited uniform nanosize and remarkable colloidal stability in aqueous solution. The sustained drug release behavior from HA micelles was observed over the test period. Moreover, the specific targeting capability based on CD44 recptor-mediated endocytosis and the enhanced targeting efficacy by in presence of external magnetic field were investigated. The clustered SPIONs within micelles exerted excellent contrast effect with high r2 relaxivity in MR phantom test. Furthermore, the multifunctional micelles could readily convert light to heat to hyperthermia temperature upon near infrared light irradition and induce photothermal ablation to breast cancer cells. The combined photothermal therapy with DTX-mediated chemotherapy of the developed multifunctional polymeric micells could generate a synergistic therapeutic effect. Based on these findings, the resulting multifunctional micelles may provide high potential for multimodality theragnosis of cancer.

Inhibiting autophagy overcomes docetaxel resistance in castration-resistant prostate cancer cells.

BACKGROUND: This study investigates the docetaxel-resistant mechanism and explores the effect of tea polyphenols (TP) on autophagy and its related mechanism in human castration-resistant prostate cancer (CRPC) cell lines PC3 and DU145. METHODS: Immunofluorescence assay and annexin V-FITC/PI double staining flow cytometry were used to analyze the apoptosis and autophagy of PC3 and DU145 cells. The expression of autophagy-related proteins was detected by western bolt. RESULTS: Docetaxel could induce autophagy and apoptosis, together with the expression increase in p-JNK, p-Bcl-2 and Beclin1. The level of autophagy was remarkably decreased, but apoptosis was increased after combining with TP. In addition, the expression of p-mTOR was increased after combining with TP. CONCLUSION: Docetaxel induces protective autophagy in CRPC cells by JNK pathway activation and then Bcl-2 phosphorylation and Beclin1 dissociation. TP activates mTOR pathway, which ultimately inhibits docetaxel-induced autophagy and improves therapeutic efficacy of docetaxel in CRPC cells.

Melatonin enhances the apoptotic effects and modulates the changes in gene expression induced by docetaxel in MCF­7 human breast cancer cells.

Results from clinical trials and multiple in vivo and in vitro studies point to melatonin as a promising adjuvant molecule with many beneficial effects when concomitantly administered with chemotherapy. Melatonin palliates side­effects and enhances the efficacy of chemotherapeutic agents. However, the mechanisms through which melatonin regulates molecular changes induced by chemotherapeutic agents remain largely unknown. In this study, we demonstrated that melatonin enhanced the anti-proliferative and apoptotic responses to low doses of docetaxel in breast cancer cells. Importantly, these effects were more potent when melatonin was added prior to docetaxel. Treatment with 1 µM docetaxel (equivalent to the therapeutic dosage) induced changes in gene expression profiles and melatonin modulated these changes. Specifically, docetaxel downregulated TP53, cyclin-dependent kinase inhibitor 1A (CDKN1A) and cadherin 13 (CDH13), and upregulated mucin 1 (MUC1), GATA binding protein 3 (GATA3) and c-MYC, whereas melatonin counteracted these effects. Melatonin further stimulated the expression of the pro-apoptotic BAD and BAX genes, and enhanced the inhibition of the anti-apoptotic gene BCL-2 induced by docetaxel. The findings of this study suggest that melatonin is a molecule with potential for use as an adjuvant in cancer chemotherapy, which may have implications for designing clinical trials using chemotherapeutic drugs in combination with melatonin.

Fungal 7-epi-10-deacetyltaxol produced by an endophytic Pestalotiopsis microspora induces apoptosis in human hepatocellular carcinoma cell line (HepG2).

BACKGROUND: Paclitaxel (taxol) is a potent anticancer drug that is used in the treatment of a wide variety of cancerous. In the present study, we identified a taxol derivative named 7-epi-10-deacetyltaxol (EDT) from the culture of an endophytic fungus Pestalotiopsis microspora isolated from the bark of Taxodium mucronatum. This study was carried out to investigate the effects of fungal EDT on cell proliferation, the induction of apoptosis and the molecular mechanisms of apoptosis in human hepatoma HepG2 cells in vitro. METHODS: The endophytic fungus was identified by traditional and molecular taxonomical characterization and the fungal EDT was purified using column chromatography and confirmed by various spectroscopic and chromatographic comparisons with authentic paclitaxel. We studied the in vitro effects of EDT on HepG2 cells for parameters such as cell cycle distribution, DNA fragmentation, reactive oxygen species (ROS) generation and nuclear morphology. Further, western blot analysis was used to evaluate Bcl-2-associated X protein (Bax), B-cell lymphoma 2 (Bcl-2), p38-mitogen activated protein kinase (MAPK) and poly [ADP-ribose] polymerase (PARP) expression. RESULTS: We demonstrate that the fungal EDT exhibited significant in vitro cytotoxicity in HepG2 cells. We investigated cytotoxicity mechanism of EDT in HepG2 cells. The results showed nuclear condensation and DNA fragmentation were observed in cells treated with fungal EDT. Besides, the fungal EDT arrested HepG2 cells at G2/M phase of cell cycle. Furthermore, fungal EDT induced apoptosis in HepG2 cells in a dose-dependent manner associated with ROS generation and increased Bax/Bcl-2 ratio, p38 MAPKs and PARP cleavage. CONCLUSIONS: Our data show that EDT induced apoptotic cell death in HepG2 cells occurs through intrinsic pathway by generation of ROS mediated and activation of MAPK pathway. This is the first report for 7-epi-10-deacetyltaxol (EDT) isolated from a microbial source.

RESILIENCE: Phase III Randomized, Double-Blind Trial Comparing Sorafenib With Capecitabine Versus Placebo With Capecitabine in Locally Advanced or Metastatic HER2-Negative Breast Cancer.

INTRODUCTION: Sorafenib is a multikinase inhibitor with antiangiogenic/antiproliferative activity. In this randomized, double-blind, placebo-controlled phase III trial, we assessed first- or second-line capecitabine with sorafenib or placebo in patients with locally advanced/metastatic HER2-negative breast cancer resistant to a taxane and anthracycline and with known estrogen/progesterone receptor status. PATIENTS AND METHODS: A total of 537 patients were randomized to capecitabine 1000 mg/m2 orally twice per day for days 1 to 14 every 21 days with oral sorafenib 600 mg/d or placebo. The primary end point was progression-free survival (PFS). Patients were stratified according to hormone receptor status, previous chemotherapies for metastatic breast cancer, and geographic region. RESULTS: Treatment with sorafenib with capecitabine, compared with capecitabine with placebo, did not prolong median PFS (5.5 vs. 5.4 months; hazard ratio [HR], 0.973; 95% confidence interval [CI], 0.779-1.217; P = .811) or overall survival (OS; 18.9 vs. 20.3 months; HR, 1.195; 95% CI, 0.943-1.513; P = .140); or enhance overall response rate (ORR; 13.5% vs. 15.5%; P = .515). Any grade toxicities (sorafenib vs. placebo) included palmar-plantar erythrodysesthesia syndrome (PPES; 79.2% vs. 59.6%), diarrhea (47.3% vs. 37.8%), mucosal inflammation (15.4% vs. 6.7%), and hypertension (26.2% vs. 5.6%). Grade 3/4 toxicities included PPES (15.4% vs. 7.1%), diarrhea (4.2% vs. 6.4%), and vomiting (3.5% vs. 0.7%). CONCLUSION: The combination of sorafenib with capecitabine did not improve PFS, OS, or ORR in patients with HER2-negative advanced breast cancer. Rates of Grade 3 toxicities were higher in the sorafenib arm.

Co-delivery of docetaxel and silibinin using pH-sensitive micelles improves therapy of metastatic breast cancer.

Breast cancer is the most vicious killer for women, and tumor metastasis is one of the leading causes of breast cancer therapy failure. In this study, a new pH-sensitive polymer (polyethylene glycol-block-poly[(1,4-butanediol)-diacrylate-ß-N,N-diisopropylethylenediamine], BDP) was synthesized. Based on BDP, docetaxel/silibinin co-delivery micelles (DSMs) was constructed. DSM had a well-defined spherical shape under the transmission electron microscope with average hydrodynamic diameter of 85.3±0.4 nm, and were stable in the bloodstream but could dissociate to release the chemotherapeutic agents in the low pH environment of the endo/lysosomes in the tumor cells. Compared with free drugs, DSM displayed greatly enhanced cellular uptake, higher cytotoxicity and a stronger anti-metastasis effect against mouse breast cancer cell line 4T1. In 4T1 tumor-bearing mice treated with DSM (twice a week for 3 weeks), the inhibition rate on tumor growth and metastasis reached 71.9% and 80.1%, respectively. These results reveal that DSM might be a promising drug delivery system for metastatic breast cancer therapy.

Combination of Nexrutine and docetaxel suppresses NFκB-mediated activation of c-FLIP.

Lack of effective options following failure to conventional chemotherapeutic agent such as Docetaxel (DX) is a major clinical challenge in the management of prostate cancer. These observations underscore the need for deciphering the underlying mechanism of DX resistance to enable the development of effective therapeutic approaches. We observed up regulation of the anti-apoptotic protein c-FLIP and its up stream regulators including receptor tyrosine kinase RON and transcription factor NFκB (p65) in tumors obtained from metastatic prostate cancer patients. We also observed significant downregulation of these molecules in prostate tumors isolated from patients treated with DX as first line therapy. Further, we identified the over the counter anti-inflammatory agent, Nexrutine (NX) suppresses c-FLIP protein levels, and expression in androgen-independent prostate cancer cells (PC-3). Remarkably, the observed decreased levels of c-FLIP were further reduced in combination with DX. Transient expression assays coupled with electrophoretic mobility shift and DNA affinity protein assay revealed that NX and DX suppresses c-FLIP promoter activity by preventing p65 binding. Notably, NX in combination with DX abolished binding of p65 to the c-FLIP promoter sequence containing NFκB binding sites. Biologically, these alterations resulted in reduced growth of PC-3 cells. Taken together, these observations suggest the utility of RON, p65, and c-FLIP as potential markers to predict response to DX treatment. Furthermore, our results also identified NX as an agent to potentiate the therapeutic response of DX by suppressing activation of c-FLIP and its upstream regulators.

P-gp modulatory acetyl-11-keto-ß-boswellic acid based nanoemulsified carrier system for augmented oral chemotherapy of docetaxel.

In spite of being a very potent and promising drug against many types of cancer, docetaxel suffers the disadvantage of low solubility and poor bioavailability rendering it unsuitable for oral administration. Also, the available marketed formulation for intravenous administration has its inherent drawbacks owing to the presence of polysorbate 80. Here, we exploited the anticancer and P-gp inhibitory potential of naturally occurring frankincense oil to fabricate a stable docetaxel loaded nanoemulsified carrier system for oral delivery. The nanoemulsion possessing desirable particle size (122±12nm), polydispersity (0.086±0.007) and zeta potential (-29.8±2.1mV) was stable against all type of physical stresses and simulated physiological conditions tested. The formulation showed higher uptake in Caco-2 cells and inhibited P-gp transporter significantly (P<0.05). In MDA-MB-231 cells, it showed less IC50, arrested cells in G2-M phase and exhibited higher degree of apoptosis than marketed formulation Taxotere®. The 182.58±4.16% increment in relative oral bioavailability led to higher in vivo anti-proliferative activity manifesting 19% more inhibition than Taxotere®. Conclusively, it is revealed that the developed nanoemulsion will be a propitious approach towards alternative docetaxel therapy.

Survival benefit of adding docetaxel, cisplatin, and 5-fluorouracil induction chemotherapy to concurrent chemoradiotherapy for locally advanced nasopharyngeal carcinoma with nodal Stage N2-3.

BACKGROUND: Concurrent chemoradiotherapy followed by adjuvant chemotherapy (CCRT-AC) has been established as the standard of care in locally advanced nasopharyngeal carcinoma (LA-NPC). The survival benefit of induction chemotherapy (ICT) for LA-NPC remains controversial. We analyzed the efficacy and feasibility of docetaxel, cisplatin and 5-fluorouracil (TPF) ICT followed by CCRT for LA-NPC with nodal Stage N2-3. METHODS: We performed a retrospective analysis of 28 LA-NPC patients with nodal Stage N2-3 receiving induction TPF followed by CCRT (TPF group; n = 12) or CCRT-AC (CCRT group; n = 16) between October 2006 and May 2016. RESULTS: The median follow-up periods were 36.4 (range 6.7-55.2) and 40.1 months (range 4.3-99.0) for the TPF and CCRT groups, respectively. One- and three-year overall survival for the TPF group vs. the CCRT group were 100% and 100% vs. 94% and 75%, respectively (P = 0.21). The cumulative one- and three-year incidences of locoregional recurrence or progression for the TPF group vs. the CCRT group were 10% and 21% vs. 16% and 32% (P = 0.49), and those of distant metastasis were 0% and 0% vs. 26% and 26%, respectively (P = 0.08). The common Grade 3-4 acute toxicities were neutropenia, anorexia, febrile neutropenia, and stomatitis in the TPF group. The Grade 3-4 late toxicities did not differ significantly between the two groups. CONCLUSIONS: This study suggests that induction TPF followed by CCRT might reduce distant metastasis, so this combination may be feasible for the treatment of LA-NPC with nodal Stage N2-3.

Polymer decorated gold nanoparticles in nanomedicine conjugates.

Noble metal, especially gold nanoparticles and their conjugates with biopolymers have immense potential for disease diagnosis and therapy on account of their surface plasmon resonance (SPR) enhanced light scattering and absorption. Conjugation of noble metal nanoparticles to ligands specifically targeted to biomarkers on diseased cells allows molecular-specific imaging and detection of disease. The development of smart gold nanoparticles (AuNPs) that can deliver therapeutics at a sustained rate directly to cancer cells may provide better efficacy and lower toxicity for treating cancer tumors. We highlight some of the promising classes of targeting systems that are under development for the delivery of gold nanoparticles. Nanoparticles designed for biomedical applications are often coated with polymers containing reactive functional groups to conjugate targeting ligands, cell receptors or drugs. Using targeted nanoparticles to deliver chemotherapeutic agents in cancer therapy offers many advantages to improve drug/gene delivery and to overcome many problems associated with conventional radiotherapy and chemotherapy. The targeted nanoparticles were found to be effective in killing cancer cells which were studied using various anticancer assays. Cell morphological analysis shows the changes occurred in cancer cells during the treatment with AuNPs. The results determine the influence of particle size and concentration of AuNPs on their absorption, accumulation, and cytotoxicity in model normal and cancer cells. As the mean particle diameter of the AuNPs decreased, their rate of absorption by the intestinal epithelium cells increased. These results provide important insights into the relationship between the dimensions of AuNPs and their gastrointestinal uptake and potential cytotoxicity. Furthermore gold nanoparticles efficiently convert the absorbed light into localized heat, which can be exploited for the selective laser photothermal therapy of cancer. We also review the emerging technologies for the fabrication of targeted gold colloids as imagining agents.