REVIEW | doi:10.20944/preprints202109.0366.v1
Subject: Medicine And Pharmacology, Oncology And Oncogenics Keywords: Docetaxel; Paclitaxel; Oncolytic Poliovirus; PVSRIPO; Sipuleucel
Online: 21 September 2021 (14:21:19 CEST)
Among the leading causes of cancer mortality, prostatic adenocarcinoma (PaC) is at second to lung carcinoma, but it is the most commonly happening non-cutaneous malignancy in elderly men in the world. Therapeutic options for PaC depend on age, growth & stage of malignancy, the desired outcomes and shortcomings of available treatment, estimated cost and patient compliance. Patients older than 60 years with a sluggish localized tumor may be placed on active surveillance, otherwise go with transurethral resection of the prostate (TURP), prostate artery embolization (PAE) and pelvic lymphadenectomy with/without radiation therapy. For metastatic PC androgen-deprivation therapy is an option with or without surgery. These agents decline the body’s testosterone production or block its activity by gonadotropin- releasing hormone (GnRH) analogues including leuprolide acetate and goserelin acetate implant. The hormone’s activity can be stopped by androgens antagonist such as flutamide, bicalutamide and nilutamide along with chemotherapeutic agents, such as taxanes (e.g., docetaxel, paclitaxel) but after all the disease relapses in 20-30% of patients. So, new immunological or vaccine-based therapeutic moieties have been investigated to meet the objective of providing selectivity to cancerous cells and desired therapeutic outcomes with less/no harmful effects to normal cells. The chimeric version, oncolytic poliovirus and human rhinovirus i.e. PVSRIPO is most promising feature in cancer therapeutics and activate innate immunity by neutrophils infiltration via PAMP & DAMP pathways while Sipuleucel-T expresses major histocompatibility complex (MHC) which can stimulate CD4+ helper T-cells and CD8+ cytotoxic T-cells and ultimately activate the acquired immunity against cancer cells. In this article, we have discussed the role of genetic predisposition and chemotherapeutic approaches including oncolytic poliovirus for the treatment of PaC in order to better understanding of tumor biology and mechanisms involved in chemotherapeutic drugs based resistance.
ARTICLE | doi:10.20944/preprints202306.1476.v1
Subject: Medicine And Pharmacology, Oncology And Oncogenics Keywords: Apoptosis; Bladder; Cancer; Microtubule; p53; Paclitaxel; Urothelium
Online: 21 June 2023 (03:50:47 CEST)
Bladder cancer (BLCA) is the sixth most common type of cancer and has a dismal prognosis if diagnosed late. To identify treatment options for BLCA, we systematically evaluated data from the Broad Institute DepMap project. We found that urothelial BLCA cell lines are among the most sensitive to microtubule assembly inhibition by paclitaxel treatment. Strikingly, we unveiled that the top dependencies in BLCA cell lines include genes encoding proteins involved in microtubule assembly, thus highlighting the importance of microtubule network dynamics as a major vulnerability in human BLCA. In cancers, such as ovarian and breast, where paclitaxel is the golden standard of care, resistance to paclitaxel treatment has been linked to p53-inactivating mutations. To study the response of BLCA to microtubule assembly inhibition and its mechanistic link with the mutational status of p53 protein, we treated a collection of BLCA cell lines with a dose range of paclitaxel and performed a detailed characterization of the response. We herein discovered that BLCA cell lines are significantly sensitive to low concentrations of paclitaxel, independently of their p53 status. Paclitaxel induced a G2/M cell cycle arrest and growth inhibition, followed by robust activation of apoptosis. Most importantly, we revealed that paclitaxel triggered a robust DNA-damage response and apoptosis program without activating the p53 pathway. Integration of transcriptomics, epigenetic and dependency data demonstrated that the response of BLCA to paclitaxel is independent of p53 mutational signatures, but strongly depends on the expression of DNA-repair genes. Our work highlights urothelial BLCA as an exceptional candidate for paclitaxel treatment and paves the way for the rational use of a combination of paclitaxel and DNA-repair inhibitors as an effective, novel therapeutic strategy.
ARTICLE | doi:10.20944/preprints201810.0231.v1
Subject: Medicine And Pharmacology, Pharmacology And Toxicology Keywords: drug release; electrospinning; paclitaxel; polycaprolactone; 3D matrix
Online: 11 October 2018 (06:09:26 CEST)
Paclitaxel is a natural, highly lipophilic anti proliferative drug widely used in medicine. We have studied the release of tritium-labeled paclitaxel (3H-PTX) from matrices destined for the coating of vascular stents and produced by the electrospinning method from the solutions of polycaprolactone (PCL) with paclitaxel (PTX) in hexafluoisoropropanol (HFIP) and/or solutions of PCL with PTX and human serum albumin (HSA) in HFIP or HIFP-dimethyl sulphoxide (DMSO) blend. The release of PTX has been shown to depend on the solvent and the composition of electrospinning solution, as well as the composition of the surrounding medium, particularly the concentration of free PTX and PTX-binding biomolecules present in human serum. It was shown that 3D matrices can completely release PTX without weight loss. Two-phase PTX release from optimized 3D matrices was obtained: ~27% of PTX was released in the first day, another 8% were released over the next 26 days. Wherein ~2.8%, ~2.3%, and ~0.25% of PTX was released on day 3, 9, and 27, respectively. Considering PTX toxicity, the rate of its diffusion through the arterial wall, and the data obtained the minimum cytostatic dose of the drug in the arterial wall will be maintained for at least three months.
ARTICLE | doi:10.20944/preprints202105.0671.v1
Subject: Medicine And Pharmacology, Immunology And Allergy Keywords: Folate-targeted nanoparticles; BSA/Alginate nanocarriers; paclitaxel; cellular uptake; cell viability.
Online: 27 May 2021 (13:55:13 CEST)
Among the different ways to reduce the secondary effects of antineoplastic drugs in cancer treatment, the use of nanoparticles has demonstrated good results due to the protection of the drug and the possibility of releasing compounds to a specific therapeutic target. The α-isoform of folate receptor (FR) is overexpressed on a significant number of human cancers; therefore, folate-targeted crosslinked nanoparticles based on BSA and alginate mixtures and loaded with paclitaxel (PTX) have been prepared to maximizing the proven antineoplastic activity of the drug against solid tumors. Nanometric-range sized particles (169 ± 28nm - 296 ± 57nm), with negative Z-potential values (between -0.12 ± 0.04 and -94.1± 0.4), were synthesized. The loaded PTX (2.63±0.19 - 3.56 ±0.13 µg PTX/mg Np) was sustainably released along 23 and 27h. Three cell lines (MCF-7, MDA-MB-231 and HeLa) were selected to test the efficacy of the folate-targeted PTX-loaded BSA/ALG nanocarriers. The presence of FR on cell membrane led to a significant larger uptake of BSA/ALG-Fol nanoparticles regarding to the equivalent nanoparticles without folic acid on its surface. The cell viability results demonstrated a cytocompatibility of unloaded nanoparticle-Fol and a gradual decrease in cell viability after treatment with PTX-loaded nanoparticles-Fol due to the sustainable PTX release.
ARTICLE | doi:10.20944/preprints202304.1122.v1
Subject: Biology And Life Sciences, Plant Sciences Keywords: plant cell culture; elicitation; methyl jasmonate; paclitaxel; plant secondary metabolism; C14-hydroxylated taxoids
Online: 28 April 2023 (05:28:39 CEST)
The effects of methyl jasmonate (MeJ) on growth and taxoid formation in the cell culture of Himalayan yew was investigated for elucidate the specifics of the action of phytohormones on dedifferentiated plant cells in vitro. The characteristics of the same suspension culture of Taxus wallichiana was compared in 2017 ("young culture") and in 2022 ("old culture") - 1.5 or 6 years after culture induction, respectively. Cells were grown in flasks and bioreactors, MeJ (100 µM) was added at the exponential growth phase. It was found that cell culture demonstrated good growth (dry weight (DW) accumulation 10–18 g/l, specific growth rate µ = 0.15–0.35 day-1) regardless of "age", cultivation system and MeJ addition. UPLC–ESI-MS analysis showed the presence of C14-hydroxylated taxoids (yunnanxane, taxuyunnanine C, sinenxane C, sinenxane B) in cell biomass in the amounts comparable to plants. The content of C14-OH taxoids during 5 years of cultivation increased by 3-5 times. It was 0.2–1.6 mg/g DW for "young culture” and 0.6-10.1 mg/g for “old culture” depending on cultivation conditions. The ratio of individual compounds changed also: in the "young culture" was predominant yunnanxane, in the "old culture" - sinenxane C. Important that C13-hydroxylated taxoids were found in trace amounts only in the "young culture” (below 0.05 mg/g DW) and were not detected in the "old culture”. The response to MeJ was radically different depending on culture’s «age». In the “young culture”, exogenous MeJ had no effect on the content of C14-OH com-pounds, but significantly (almost 10 times) increased the content of C13-OH compounds. In particular, paclitaxel concentration was elevated up to 0.12–0.19 mg/g DW, which is comparable to its content in the bark of yew trees. By contrast, MeJ added to the "old culture” had minor effect on the synthesis of C13-OH toxoids that appeared in trace amounts only (below 3.5 µg/g DW for paclitaxel) but notably increased the content of C14-OH compounds (1.5–2.0 times in flasks and 5–8 times in bioreactors). These findings suggest that hormonal signaling in dedifferentiated yew cells grown in vitro is different from that in plants and change with culture age. This might be a result of the high level of heterogeneity of cells in vitro and their constant auto-selection for proliferate intensity which leads to predominant formation of C14-OH taxoids versus C13-OH taxoids and modified cell response to exogenous MeJ treatment. These results have both fundamental and practical biotechnological application.
ARTICLE | doi:10.20944/preprints202306.1494.v1
Subject: Medicine And Pharmacology, Oncology And Oncogenics Keywords: microgravity; chemotherapy; paclitaxel; hydroxyurea; morphometry; drug response; immune dysfunction; space medicine; terrestrial medicine; fluorescence microscopy
Online: 21 June 2023 (07:34:49 CEST)
Unlike plants which have special gravity-sensing cells, such special cells in animals are yet to be discovered. However, microgravity, the condition of apparent weightlessness, causes bone, muscular and immune system dysfunctions in astronauts following spaceflights. Decades of investigations show correlations between these organ and system-level dysfunctions with changes induced at the cellular level both by simulated microgravity as well as microgravity conditions in outer space. Changes in single bone, muscle and immune cells include morphological abnormalities, altered gene expression, protein expression, metabolic pathways and signaling pathways. These suggest that human cells mount some response to microgravity. However, the implications of such adjustments on many cellular functions and responses are not clear. Here, we addressed the question whether microgravity induces alterations to drug response in cancer cells. We used both adherent cancer cells (T98G) and cancer cells in suspension (K562) to confirm known effects of microgravity and then treated the K562 cells with common cancer drugs (hydroxyurea and paclitaxel) following 48 hours of exposure to microgravity via a NASA-developed rotary cell culture system. Fluorescence-guided morphometry revealed microgravity-induced loss of the significant reduction (p < 0.0l) to the nuclear to cytoplasm ratio of cancer cells treated with hydroxyurea. Our results call for more studies on impact of microgravity on cellular drug-response, in view of the growing need for space medicine, as space exploration grows.
ARTICLE | doi:10.20944/preprints201804.0307.v1
Subject: Medicine And Pharmacology, Oncology And Oncogenics Keywords: gastric cancer; ramucirumab; paclitaxel; second line therapy; vascular endothelial growth factor receptor 2; targeted therapy; nutrition
Online: 24 April 2018 (06:01:56 CEST)
The RAINBOW Phase III study established the efficacy of the combination of paclitaxel and ramucirumab, a monoclonal antibody targeting VEGF receptor-2 (VEGF-R2), as second-line therapy. We retrospectively analyzed the data of patients treated with ramucirumab plus paclitaxel at our Institution to evaluate the impact of clinical heterogeneous figures on the efficacy and safety of this combination paclitaxel/ramucirumab in a real- life cohort of patients. After a median follow-up of 10.74 months, the median progression-free survival (PFS) was 5.8 months (95% CI: 3.04 - 5,63). Disease control rate (DCR) was 61% and the median duration of response (DOR) was 5.8 months. Median overall survival (OS) was 8.3 months. A trend toward better outcome was observed in HER2 positive patients. In multivariate analysis, nutritional status (p = 0.0001) and number of metastatic sites (p = 0.0266) resulted significantly related with longer PFS. Our analysis confirmed the efficacy and safety of the combination of ramucirumab with paclitaxel also in the real-life practice and the median PFS is significantly longer than that reported for Western population in previous studies. Subgroup analysis confirms the key-role of nutritional status as prognostic factor and suggests a possible interaction between EGF and angiogenesis pathways that deserves further investigations.
ARTICLE | doi:10.20944/preprints201704.0023.v1
Subject: Chemistry And Materials Science, Nanotechnology Keywords: gelatin-oleic conjugate; self-assembled biodegradable nanoparticles; biomimetic shear stress; cell dynamic environment; cellular drug delivery; paclitaxel
Online: 4 April 2017 (10:59:02 CEST)
Fluid flow in human body is generally known to influence a variety of cellular behaviors. Different nanoparticle properties as well as cell type, interaction with other cells and cellular environments also show significant effect on nanoparticle uptake and drug efficacy. The aim of this study was to evaluate the effect of shear stress on cellular behaviors of biocompatible and biodegradable nanoparticles to cancer cells (A549 cell lines) in a biomimetic microfluidic system. We prepared a gelatin-oleic conjugate (GOC) as an amphiphilic biomaterial to prepare self-assembled gelatin-oleic nanoparticles (GON). Coumarin-6 and paclitaxel were used as the fluorescence marker and model drug, respectively, and were loaded into GONs by incubation (C-GONs; PTX-GONs). Additionally, we evaluated the cellular uptake of fluorescence labeled C-GONs and the drug efficacy of PTX-GONs. The cellular uptake of C-GONs by A549 cells in the absence of shear stress revealed that the mean fluorescence intensity was slightly decreased compared to that in the presence of shear stress. The results also indicated that negatively charged PTX-GONs had a lower cancer killing effect under dynamic conditions than that under static conditions. It also suggested that fluidic shear stress did not significantly affect drug uptake and efficiency in case of PTX-GONs. The cellular interactions between nanoparticles and cells in drug delivery should be carefully examined according to the physicochemical properties of nanoparticles such as the type of materials, size and mainly surface charge in a biomimetic microfluidic condition.
ARTICLE | doi:10.20944/preprints202103.0777.v1
Subject: Biology And Life Sciences, Biochemistry And Molecular Biology Keywords: Exosomal PD-L1 mRNA; extracellular vesicles; Triple Negative Breast Cancer; Immunotherapy; PD-L1 axis; Atezolizumab – nab-paclitaxel; Predictive biomarkers; Liquid biopsy
Online: 31 March 2021 (15:27:45 CEST)
Patients diagnosed with unresectable locally advanced Triple Negative Breast Cancer (TNBC) usually have poor outcome for its aggressive clinical behaviour. Atezolizumab plus nanoparticle albumin-bound (nab)-Paclitaxel prolonged progression-free survival (PFS) and overall survival (OS) among patients with unresectable locally advanced TNBC but its use is hampered by the lack of reliable predictors of tumor response. Seventy-seven consecutive patients with unresectable locally advanced TNBC treated with Atezolizumab plus nab-Paclitaxel were studied by blood draws at baseline, 28 days and 56 days after initiation of treatment. Exosomal PD-L1 mRNA in plasma was determined using Bio-Rad QX100 digital droplet PCR system and exoRNeasy kit and objective responses were defined following the RECIST criteria v.1.1. The study evaluates whether PD-L1 mRNA copies per ml in plasma-derived exosomes may predict response to anti-PD-L1 antibodies early in the course of therapy. Our data showed patients with unresectable locally advanced TNBC and higher levels of PD-L1 mRNA expression in plasma-derived exosomes at baseline demonstrated greater response to atezolizumab plus nab-paclitaxel. Furthermore, the levels of mRNA decreased with successful treatment while the copy number increased in patients experiencing disease progression following atezolizumab plus nab-paclitaxel. For the first time, our data showed the usefulness of assessment of exosomal PD-L1 as non-invasive real-time biopsy in patients diagnosed with TNBC suggesting exosomal PD-L1 is significantly associated with outcome and response to Atezolizumab plus nab-Paclitaxel.