Formulations Of Anticancer Drugs Research Articles

Pluronic-coated hydroxypropyl-β-cyclodextrin nanoparticle potentiated chemotherapy on multidrug resistance cancer cells via improved docetaxel loading and P-glycoprotein inhibition

In the pharmaceutical formulation of anticancer drugs, US FDA-approved cyclodextrin (CD) and its derivates have been widely employed. Among them, hydroxypropyl β-cyclodextrin (HPCD) has attracted considerable attention owing to low toxicity, improved water solubility, and enhanced drug absorption; however, HPCD exhibits low drug loading efficiency and poor anticancer efficacy in multidrug-resistant (MDR) cancer cells. Therefore, to improve the drug loading efficiency and simultaneously overcome the MDR effects, we developed docetaxel (DTX)-loaded Pluronic®(PLU)-coated hydroxypropyl-β-cyclodextrin nanoparticles (DTX@PLU/HPCD NPs). We employed a simple nanoprecipitation technique, wherein PLU acted as a P-glycoprotein inhibitor to overcome MDR and an enhancer to achieve high drug loading. The HPCD NPs were coated with PLU (PF127, PP123, and PL81) of varying hydrophilic/lipophilic balance values, and the amount of encapsulated DTX was optimized. The DTX-loaded HPCD formulations (DTX@HPCD NP, DTX@PF127/HPCD NP, and DTX@PP123/HPCD NP) exhibited good stability and facilitated sustained release. The HPCD formulations exerted no cytotoxicity against examined cancer cell lines (HCT15 and SCC 7). DTX@PLU/HPCD NPs exerted potent anticancer effects in vitro. Notably, DTX@PP123/HPCD NPs significantly reduced the tumor volume in a mouse model. Collectively, these results indicate that PLU/HPCD NPs could function as drug carriers to alleviate toxicity and overcome MDR in various cancer models.

Disulfide Cross-Linked Polymeric Redox-Responsive Nanocarrier Based on Heparin, Chitosan and Lipoic Acid Improved Drug Accumulation, Increased Cytotoxicity and Selectivity to Leukemia Cells by Tumor Targeting via "Aikido" Principle.

We have developed a micellar formulation of anticancer drugs based on chitosan and heparin grafted with lipoic and oleic acids that can release the cytotoxic cargo (doxorubicin) in response to external stimuli, such as increased glutathione concentration-a hallmark of cancer. Natural polysaccharides (heparin and chitosan) provide the pH sensitivity of the nanocarrier: the release of doxorubicin (Dox) is enhanced in a slightly acidic environment (tumor microenvironment). Fatty acid residues are necessary for the formation of nanoparticles (micelles) and solubilization of cytostatics in a hydrophobic core. Lipoic acid residues provide the formation of a labile S-S cross-linking between polymer chains (the first variant) or covalently attached doxorubicin molecules through glutathione-sensitive S-S bridges (the second variant)-both determine Redox sensitivity of the anticancer drugs carriers stable in blood circulation and disintegrate after intracellular uptake in the tumor cells. The release of doxorubicin from micelles occurs slowly (20%/6 h) in an environment with a pH of 7.4 and the absence of glutathione, while in a slightly acidic environment and in the presence of 10 mM glutathione, the rate increases up to 6 times, with an increase in the effective concentration up to 5 times after 7 h. The permeability of doxorubicin in micellar formulations (covalent S-S cross-linked and not) into Raji, K562, and A875 cancer cells was studied using FTIR, fluorescence spectroscopy and confocal laser scanning microscopy (CLSM). We have shown dramatically improved accumulation, decreased efflux, and increased cytotoxicity compared to doxorubicin control with three tumor cell lines: Raji, K562, and A875. At the same time, cytotoxicity and permeability for non-tumor cells (HEK293T) are significantly lower, increasing the selectivity index against tumor cells by several times.

Repurposing the antihistamine drug bilastine as an anti-cancer metallic drug entity: synthesis and single-crystal X-ray structure analysis of metal-based bilastine and phen [Co(II), Cu(II) and Zn(II)] tailored anticancer chemotherapeutic agents against resistant cancer cells.

Bilastine (BLA), 2-(4-(2-(4-(1-(2-ethoxyethyl)-1H-benzo[d]imidazole-2-yl)-piperidin-1-yl)-ethyl)-phenyl)-2-methylpropanoic acid, is an active antihistamine drug. With the idea of repurposing drugs from the existing pool of 'active' pharmaceutical ingredients, the therapeutic potency of bilastine as an anticancer agent was investigated via the tailored synthesis of a metal-based anticancer drug formulation of the type [BLA(phen)2M(II)]+·X-, where M = Co, Cu, and Zn and X- = NO3 and ClO4. The synthesized metal-based chemotherapeutics derived from the bilastine drug that acts as a ligand were thoroughly characterized using spectroscopic techniques, namely, UV-vis, FT-IR, and EPR (in the case of 1 and 2); 1H-NMR and 13C-NMR (in the case of 3); ESI-MS and single-crystal X-ray diffraction studies. Comprehensive biological studies (DNA binding, cleavage, and cytotoxic activity) using various biophysical and gel electrophoretic methods were carried out to validate their potential as anticancer agents. The cytotoxic activity of 'therapeutically promising' copper(II)-based drug candidate 2 was evaluated against MCF-7, MBA-MD-231, HeLa, HepG2, and Mia-PaCa-2 cancer cells via an SRB assay, and the results demonstrated 2 as a potent anticancer agent at low nanomolar concentrations against all tested cancer cells, preferably with a much superior anticancer efficacy against human pancreatic cancer cells.

Isolation and characterization of 2,4-di-tert-butyl phenol from the brown seaweed, Dictyota ciliolata and assessment of its anti-oxidant and anticancer characteristics

The current study pertains to the evaluation of the 2,4-di-tert-butyl phenol (2,4 DTBP) compound from the brown seaweed, Dictyota ciliolata against the MCF-7 breast cancer cell line. The 2,4-DTBP was confirmed by the spectral characterization of the HPLC, FTIR, 1H NMR and 13C NMR. The DPPH antioxidant assay of the 2,4-DTBP revealed that the fractioned compound possesses higher antioxidant content of 59.02 % with the IC50 value of 56.61 μL when compared to the standard ascorbic acid. Presently, the 2,4-DTBP had exhibited cytotoxicity as it induced the apoptosis process against MCF-7 with the IC50 value of 70 μM. Molecular docking analysis showed that 2,4-DTBP exhibited high binding affinity with carbonic anhydrase IX enzyme with good docking score (−6.7 to −6.2 kcal/mol). The non-target, Artemia toxicity assay using 2,4-DTBP revealed only low toxicity rate with the LC50 value (μg/mL) of 198.93, after 24 h treatment. The present study provides some insights into the medicinal and pharmaceutical properties of the 2,4-DTBP with special reference to the breast cancer cell-apoptosis. The presently generated baseline data would form important basis for further research on 2,4-DTBP towards anticancer drug formulation in future.

Natural polymers as potential P-glycoprotein inhibitors: Pre-ADMET profile and computational analysis as a proof of concept to fight multidrug resistance in cancer

P-glycoprotein (P-gp) is known as the "multidrug resistance protein" because it contributes to tumor resistance to several different classes of anticancer drugs. The effectiveness of such polymers in treating cancer and delivering drugs has been shown in a wide range of in vitro and in vivo experiments. The primary objective of the present study was to investigate the inhibitory effects of several naturally occurring polymers on P-gp efflux, as it is known that P-gp inhibition can impede the elimination of medications. The objective of our study is to identify polymers that possess the potential to inhibit P-gp, a protein involved in drug resistance, with the aim of enhancing the effectiveness of anticancer drug formulations. The ADMET profile of all the selected polymers (Agarose, Alginate, Carrageenan, Cyclodextrin, Dextran, Hyaluronic acid, and Polysialic acid) has been studied, and binding affinities were investigated through a computational approach using the recently released crystal structure of P-gp with PDB ID: 7O9W. The advanced computational study was also done with the help of molecular dynamics simulation. The aim of the present study is to overcome MDR resulting from the activity of P-gp by using such polymers that can inhibit P-gp when used in formulations. The docking scores of native ligand, Agarose, Alginate, Carrageenan, Chitosan, Cyclodextrin, Dextran, Hyaluronic acid, and Polysialic acid were found to be −10.7, −8.5, −6.6, −8.7, −8.6, −24.5, −6.7, −8.3, and −7.9, respectively. It was observed that, Cyclodextrin possess multiple properties in drug delivery science and here also demonstrated excellent binding affinity. We propose that drug efflux-related MDR may be prevented by the use of Agarose, Carregeenan, Chitosan, Cyclodextrin, Hyaluronic acid, and/or Polysialic acid in the administration of anticancer drugs.

Development and validation of apalutamide-related substances method in solid dosage forms using HPLC.

A related-substances method was developed for the anticancer drug formulation apalutamide 60 mg tablets and validated using a liquid chromatography gradient elution method. All of the impurities and degradants were separated using the Luna Omega 5μm Polar C18 , (250 × 4.6) mm HPLC column with a 1.0 ml min-1 flow rate. The detection was done at 225 nm by injecting the 10μl of injection volume, controlling the sample temperature at 10°C and maintaining the column compartment temperature at 30°C. The total run time was 85 min. A 0.01m disodium phosphate dihydrate pH4.20 ± 0.05 buffer mixed with acetonitrile in the ratio of 73:27 (v/v) was used as mobile phase A. Mobile phase B consisted of water and acetonitrile in the ratio 30:70 (v/v). The proposed method was validated as per the current regulatory guidelines. The method precisions (RSD) at 100% specification level were 1.41, 1.74, 1.84, and 1.66% for the four impurities. The accuracy results were obtained between 96.0 and 106.3% for the limit of quantitation to the 150% level. The standard and sample solutions stability were established for 44 h at 10°C. The correlation coefficient (r) value was >0.999 for all four impurities, indicating good linearity between the concentration and peak response: 0.9999, 0.9999, 0.9999 and 1.0000. These results show the method's linearity. The three filter compatibility was proved and it was concluded that 0.45 μm Nylon, PTFE and PVDF filters are suitable. The robustness of the method was established by varying the conditions. The method specificity was proved and the forced degradation data reveal the method's stability-indicating nature.

Cyclodextrin-Based Arsenal for Anti-Cancer Treatments.

Anti-cancer drugs are mostly limited in their use due to poor physicochemical and biopharmaceutical properties. Their lower solubility is the most common hurdle limiting their use upto their potential. In the recent years, the cyclodextrin (CD) complexation have emerged as existing approach to overcome the problem of poor solubility. CD-based nano-technological approaches are safe, stable and showed well in vivo tolerance and greater payload for encapsulation of hydrophobic drugs for the targeted delivery. They are generally chosen due to their ability to get self-assembled to form liposomes, nanoparticles, micelles and nano-sponges etc. This review paper describes a birds-eye view of the various CD-based nano-technological approaches applied for the delivery of anti-cancer moieties to the desired target such as CD based liposomes, niosomes, niosoponges, micelles, nanoparticles, monoclonal antibody, magnetic nanoparticles, small interfering RNA, nanorods, miscellaneous formulation of anti-cancer drugs containing CD. Moreover, the author also summarizes the various shortcomings of such a system and their way ahead.

Oral administration of sodium bicarbonate can enhance the therapeutic outcome of Doxil® via neutralizing the acidic tumor microenvironment.

The pH of the tumor microenvironment in solid tumors is reported to be more acidic than that of normal tissues. The pH is controlled by over-expression of several transporters that are associated with the progression, angiogenesis, and metastasis of solid tumors. Antitumor effects of weak-base anticancer agents, such as doxorubicin (DXR), could be reduced in an acidic environment because of increases in the ionized form of the drug under these conditions, reducing its membrane penetrability. In our previous studies, we demonstrated that oral administration of sodium bicarbonate (NaHCO3) can neutralize the acidic tumor microenvironment and enhance the effects of small molecule anticancer drugs. However, it is not known whether or not increasing the tumor pH by oral administration of NaHCO3 leads to enhanced antitumor effects of lipidic nanoparticle formulations of weak-base anticancer drugs, such as Doxil®. In this study, we investigated the antitumor efficacy of Doxil® in combination with oral administration of NaHCO3 in a Colon26 tumor-bearing mouse model. NaHCO3 clearly enhanced the tumor-growth inhibitory effect of Doxil® without exacerbating any systemic side effects. In vitro studies indicated that high levels of DXR were internalized into cells at neutral pH. These studies demonstrate that the neutralization of acidic tumor microenvironment by an oral administration of NaHCO3 could be a promising approach to enhance the therapeutic outcomes of Doxil®.

Indispensable role of microbes in anticancer drugs and discovery trends.

Recent years have seen an increased focus on the advancement of naturally derived products for the treatment of cancer. Since the beginning of recorded history, nature has provided a variety of medicinal agents, and an overwhelming number of drugs that we have today are derived from natural sources. Such natural agents are prominently used to treat several diseases such as diabetes, malaria, Alzheimer's, pulmonary disorders, etc. with cancer being the highlight of this review. Due to the rapid development of resistance to chemotherapeutic drugs, the hunt for effective novel drugs is still a paramount concern in cancer treatment. Moreover, many chemotherapy drugs typically have high toxicity and adverse side effects, which necessitates the need to develop anti-tumor drugs that can be employed to treat deadly tumors with fewer negative effects on health and better efficacy. Isolation of several chemotherapeutic drugs has been conducted from a wide range of natural sources which include plants, microbes, fungi, and marine microorganisms. Considering the trends of previous decades, microbial diversity has grown to play a significant role in the formulation of pharmaceuticals and drugs, especially antibiotics and anti-cancer medications. Microbe-derived antitumor antibiotics such as anthracycline, epothilones, bleomycin, actinomycin, and staurosporine are amongst the widely used cancer chemotherapeutic agents. This review deals majorly with microbe-derived anticancer drugs taking into account their derivatives, mechanism of action, isolation procedures, limitations, and tumors targeted by them. This article also reports the phase of clinical study these drugs are undergoing. Moreover, it intends to portray the indispensable part that these microbes have been playing since time immemorial in the odyssey of chemotherapeutic agents. KEY POINTS: • Microbial diversity contributes heavily towards the formulation of anticancer drugs. • Polypeptides, carbohydrates, and alkaloids are prevalent microbe-based drug classes. • Microbe-derived anticancer agents target various sarcomas, carcinomas, and lymphomas.

Quantitative comparison of anticancer drug dispersal before and after introducing appropriate preparation procedures during anticancer drug preparation

BackgroundIn Japan, engineering controls for preparing injectable anticancer drugs are inadequate and compliance with appropriate preparation procedures is vital. In this study, we evaluated the effects of adherence to appropriate anticancer drug formulation and packaging procedures on reducing anticancer drug dispersal in clinical practice, especially in Japan.MethodsWe quantitatively evaluated the effectiveness of implementing procedures that were experimentally verified to help reduce the amount of anticancer drug dispersed during preparation based on procedures described in the “Anticancer Drug Preparation Manual.” The target facilities were four regional hub hospitals in the Kanto area. Contamination of sheets and gloves with 5-fluorouracil (5-FU) and gemcitabine (GEM) in a safety cabinet during formulation was evaluated using wipe tests. Subsequently, the proper preparation procedure was shown on a video, training was provided, and the wipe tests were repeated.ResultsForty-one and 39 pharmacists were engaged in drug preparation before and after intervention, respectively. 5-FU had the highest dispersal per prepared vial on the sheet before intervention. The dispersal amount per prepared vial decreased significantly (P = 0.01) after intervention. The amount of GEM dispersed before and after intervention did not differ significantly. However, the percentage of sheets below the detection limit after intervention was 62%, increasing from 46% before intervention. The amount dispersed on gloves was not significantly reduced by proper preparation technique. Although not explicitly noticeable and quantifiable, pharmacists must consider that a significant amount of anticancer drug is dispersed on gloves despite following appropriate preparation procedures.ConclusionsQuantitative amounts of anticancer drugs dispersed in the preparations of 5-FU and GEM were found in our study. The difference in the amount of contamination before and after intervention was significantly reduced only for the contamination of sheets with 5-FU. There was no decrease in the amount of glove contamination. There was also no difference between medical facilities. Despite following appropriate preparation procedures, dispersed amounts cannot be maintained below the detection limit, indicating the need for a combination of education and engineering controls.

EXPLORING LIPID-BASED DRUG DELIVERY IN CANCER THERAPY VIA LIPOSOMAL FORMULATIONS

In many countries across the world, cancer is a leading cause of death. Cancer is the biggest cause of death worldwide, with approximately 10 million fatalities expected in 2020, accounting for nearly one in every six deaths. Mutations in ~300 human genes can unleash cell division, potentially leading to cancer. The effectiveness of existing conventional therapies for a number of cancers is, however, inefficient in terms of safety and efficacy. Medication systems based on lipid can be configured to treat tumors passively with increasing safety by reducing toxicity and increasing efficacy by target drug delivery. Lipid-based drug dosage form is the new identified technological design to overcome problems such as water-soluble solubility and bioavailability. A wide range of product specifications determined by indication of disease, route of administration, price evaluation, safety, toxicity, and efficiency could be customized to lipid formulations. This analysis explores the current state of lipid drug delivery studies, including the production of cancer liposomes, different cancer-focused strategies, and liposomal formulation of numerous anti-cancer drugs.

The First tetrafluorinated azobenzene-imidazolium ionic conjugates as potential thermotropic liquid crystalline drugs: Self-assembly properties and cytotoxic effects

A new series of tetrafluorinated azobenzene-imidazolium ionic liquid crystals (ILCs) of varying alkyl chain length (n = 10–18 in even parity) in the imidazolium cationic head group was prepared and characterized using FTIR and NMR spectroscopy, and elemental microanalysis. Their thermal and phase properties were investigated using differential scanning calorimetry (DSC) and polarized optical microscope (POM). Their phase properties and morphology were influenced by fluorination and alkyl chain length. Long alkyl chains were necessary to induce liquid crystalline behaviour in these salts. All homologues were mesogenic, exhibiting stable smectic A phase with broad temperature range. Cytotoxic effects of these ILCs against human cervical cancer (HeLa) cells and normal fibroblasts was evaluated using the MTT assay. Cytotoxicity of these ILCs was dependent on the alkyl chain length in the imidazolium cationic head. All the salts were less toxic towards normal fibroblasts and exhibited 7–27-fold enhancement in cytotoxicity against HeLa cells (24hr IC50 ranged between 0.61 µM -2.84 µM) as compared to the standard therapeutic drug, Etoposide (IC50 = 25.67 µM). Long homologues (n = 16, 18) were selective towards cancer cells with selectivity index ≥ 3. These thermotropic ILCs could be doped with room-temperature mesomorphous polymers for the formulation of safe and selective anticancer drugs.

SPARC-mediated long-term retention of nab-paclitaxel in pediatric sarcomas

Secreted protein acidic and rich in cysteine (SPARC) is a matricellular glycoprotein overexpressed by several cancers. Because SPARC shows high binding affinity to albumin, we reasoned that pediatric sarcoma xenografts expressing SPARC would show enhanced uptake and accumulation of nanoparticle albumin-bound (nab)-paclitaxel, a potent anticancer drug formulation. We first evaluated the expression of SPARC in patient-derived xenografts (PDXs) of Ewing sarcoma, rhabdomyosarcoma and osteosarcoma, finding variable SPARC gene expression that correlated well with SPARC protein measured by immunoblotting. We revealed that the activity of the fusion gene chimera EWSR1-FLI1, the genetic driver of Ewing sarcoma, leads to lower expression of the gene SPARC in these tumors, likely due to enriched acetylation marks of the histone H3 lysine 27 at regions including the SPARC promoter and potential enhancers. Then, we used SPARC-edited Ewing sarcoma cells (A673 line) to demonstrate that SPARC knocked down (KD) cells accumulated significantly less amount of nab-paclitaxel in vitro than SPARC wild type (WT) cells. In vivo, SPARC KD and SPARC WT subcutaneous xenografts in mice achieved similar maximum intratumoral concentrations of nab-paclitaxel, though drug clearance from SPARC WT tumors was significantly slower. We confirmed such SPARC-mediated long-term intratumoral accumulation of nab-paclitaxel in Ewing sarcoma PDX with high expression of SPARC, which accumulated significantly more nab-paclitaxel than SPARC-low PDX. SPARC-high PDX responded better to nab-paclitaxel than SPARC-low tumors, although these results should be taken cautiously, given that the PDXs were established from different patients that could have specific determinants predisposing response to paclitaxel. In addition, SPARC KD Ewing sarcoma xenografts responded better to soluble docetaxel and paclitaxel than to nab-paclitaxel, while SPARC WT ones showed similar response to soluble and albumin-carried drugs. Overall, our results show that pediatric sarcomas expressing SPARC accumulate nab-paclitaxel for longer periods of time, which could have clinical implications for chemotherapy efficacy.

Host-guest inclusion systems of two bioactive natural products derivantives and three polyamine-modified β-cyclodextrins: Preparation, characterization, biological activity

Two bioactive natural products derivatives including hydroxycamptothecin (HCPT) and etoposide (EPEG), which are one of the most common classes of first-line anticancer drugs used for the treatment of cancer. Of note, their application is still limited by poor water solubility and bioavailability. Therefore, it is very important to develop a new means to solve these shortcomings. In this work, the molecular binding behavior of three polyamine-modified β-cyclodextrins (H1-3) with HCPT and EPEG was investigated. The six novel H1-3/HCPT (EPEG) inclusion complexes were prepared and characterized by Fourier transform infrared spectrometry (FTIR), 2D nuclear magnetic resonance (2D ROESY), 1H nuclear magnetic resonance (NMR), X-ray powder diffraction (XRD) and scanning electron microscopy (SEM). The phase solubility diagrams indicated that the stability constants (K1:1) of host H1-3 to the free drugs decrease sequentially as follows: H3>H2>H1. After forming inclusion complexes with H1-3, the water solubility of HCPT (EPEG) were obviously increased from the initial value of 0.0011 mg/mL (0.373 mg/mL) to 0.90 mg/mL (32.55 mg/mL), 2.01 mg/mL (38.73 mg/mL), and 2.39 mg/mL (47.42 mg/mL), enhanced by 84.9–225.5 times compared with the free drug, respectively. The in vitro release tests confirmed that the cumulative release of drug from H1-3/EPEG (HCPT) complexes was significantly higher than that from free drug solution in 50 h. The cytotoxicity assay showed that the H1/HCPT exhibited higher cytotoxicity towards MCF-7 cell in comparison to the free drug HCPT. Meanwhile, the toxicity of HCPT is obviously reduced after the formation of H2/HCPT. Apoptosis experiments revealed that the percentage of apoptotic cells was increased by H3/HCPT (65.80%), which close to increasing by free drugs HCPT (74.00%) when the concentrations of H3/HCPT and HCPT reached to a certain level (5.0 μg/mL). The satisfactory water solubility, high activity, and low toxicity of H1-3/HCPT (EPEG) inclusion complexes contributes to research with new applications of the HCPT and EPEG as anticancer drug formulations.

Anticancer Mechanisms of Bioactive Compounds from Solanaceae: An Update.

Simple SummaryThe Solanaceae plant family has been a good source of natural compounds that can treat several diseases, including cancer. However, the site and mechanism of action of these compounds in cells has not been entirely clear. With ongoing developments in biological science research, it has become possible to study and identify some of the cellular targets. In this review, we assess publications from the last five years and identify research articles that explain how some of these compounds may work against cancer. These studies show that a number of different components or pathways in cells are targeted by these compounds to inhibit cell proliferation. Interestingly, some compounds have multiple targets and may be effective against different types of cancer. This knowledge may allow scientists to design new and more effective anticancer drugs.Plants continue to provide unlimited pharmacologically active compounds that can treat various illnesses, including cancer. The Solanaceae family, besides providing economically important food plants, such as potatoes and tomatoes, has been exploited extensively in folk medicine, as it provides an array of bioactive compounds. Many studies have demonstrated the anticancer potency of some of the compounds, but the corresponding molecular targets are not well defined. However, advances in molecular cell biology and in silico modelling have made it possible to dissect some of the underlying mechanisms. By reviewing the literature over the last five years, we provide an update on anticancer mechanisms associated with phytochemicals isolated from species in the Solanaceae plant family. These mechanisms are conveniently grouped into cell cycle arrest, transcription regulation, modulation of autophagy, inhibition of signalling pathways, suppression of metabolic enzymes, and membrane disruption. The majority of the bioactive compounds exert their antiproliferative effects by inhibiting diverse signalling pathways, as well as arresting the cell cycle. Furthermore, some of the phytochemicals are effective against more than one cancer type. Therefore, understanding these mechanisms provides paths for future formulation of novel anticancer drugs, as well as highlighting potential areas of research.

2-Methoxy-estradiol Loaded Alpha Lipoic Acid Nanoparticles Augment Cytotoxicity in MCF-7 Breast Cancer Cells.

The therapeutic effectiveness of anticancer drugs with a selective target for the nucleus of cancer cells may be improved by experimental approaches. In this regard, the formulation of anticancer drugs is considered one of the best ways to improve their effectiveness in targeting cancerous tissues. To enhance the anticancer activity of 2-methoxy-estradiol (2 ME) for breast cancer, 2-methoxyestradiol loaded alpha lipoic acid nanoparticles have been formulated. The prepared formula was observed to be spherical with a nanometer-scale and low PDI size (.234). The entrapment efficiency of the 2ME-ALA NPs was 87.32 ± 2.21% with > 85% release of 2 ME within 24 h. There was a 1.2-fold increase in apoptosis and a 3.46-fold increase in necrosis of the MCF-7 cells when incubated with 2ME-ALA NPs when compared to control cells. This increased apoptosis was also associated with increased ROS and increased p53 expression in 2ME-ALA NPs treated cells compared to the raw-2 ME group. Evaluation of cell-cycle data showed a substantial arrest of the G2-M phase of the MCF-7 cells when incubated with 2ME-ALA NPs. At the same time, a dramatically increased number of pre-G1 cells showed the increased apoptotic potential of the 2 ME when administered via the proposed formulation. In the end, the differential upregulation of caspase-3, p53, and ROS in MCF-7 cells established the superiority of the 2ME-ALA-Ms approach in targeting breast cancer. In summary, these results demonstrate that 2ME-ALA NPs are an efficient delivery tool for controlling the growth of breast cancer cells.

Glycyrrhizin Mediates Downregulation of Notch Pathway Resulting in Initiation of Apoptosis and Disruption in the Cell Cycle Progression in Cervical Cancer Cells

Growing emphasis on exploring the antiproliferative potential of natural compounds has gathered momentum for the formulation of anticancer drugs. In the present study, the anticancer and apoptotic potential of glycyrrhizin (GLY) was studied on HPV– C33A cervical cancer (CCa) cells. Our results indicated that GLY exerted antiproliferative effects in the C33A cells by inducing significant cytotoxicity. Treatment with GLY substantially increases the apoptosis in a dose-dependent manner via disrupting the mitochondrial membrane potential. GLY induced apoptosis in C33A cells via activation of capsase-9 (intrinsic pathway) and caspase-8 (extrinsic pathway) along with the modulation of pro- and antiapoptotic protein expression. Moreover, GLY also exerted cell cycle arrest in C33A cells at G0/G1 phase which was associated with the decreased expression of cyclin D1 and cyclin-dependent kinase 4 (CDK4) along with the increased expression of CDK inhibitor p21Cip1. Furthermore, GLY treated CCa cells exhibited significant downregulation of Notch signaling pathway which may be associated with increased apoptosis as well as cell cycle arrest in C33A CCa cells. Thus, GLY could be an appendage in the prevention and management of CCa.

Targets and Mechanism of Action of Chemical constituents from Plants with Potential Anti-leukemic Activity

The plant kingdom has been the most significant source of anticancer drugs. These include alkaloids, diterpenes, tannins, phenolics, lignans, glycosides which have exhibited lesser toxicity than conventional drugs. In leukaemia, the human body is susceptible to infections due to the replacement of normal leucocytes replaced by a large number of immature cells. Chemotherapy for leukaemia is associated with side effects and drug resistance by the leukemic cells. Cytotoxic agents with higher efficacy and lesser side effects are good candidates in cancer therapy, and plant metabolites serve as potential bioactive agents in anticancer drug formulations. This review article discusses the anti-leukemic properties of compounds obtained from plants and the mechanism of anti-leukemic activity induced by each of these plants. Effect of plants and their metabolites on different leukemic cell lines such as HL60, Kasumi-1, CCRF-CEM, K-562, U-937, THP-1 and MOLT-3 was compared. The findings showed anti-leukemic activity through cell cycle arrest, DNA damage, destruction of mitochondrial function, suppression of tumour genes, apoptosis-inducing enzymes and cytotoxic activities of plants and their derivatives. Based on extensive research findings from this review, phytochemicals and their derived analogues possess the most promising option for the better and less toxic anti-leukemic treatment. Identification of the mechanism of action by the plant bioactive compounds helps in developing standard herbal medicines for effective leukaemia treatment.

Benzimidazole-Based Organic-Inorganic Gold Nanohybrids Suppress Invasiveness of Cancer Cells by Modulating EMT Signaling Cascade.

Over the past few years, nanotechnology-based approaches have emerged to override drug resistance owing to their superiority over other formulations because of their diverse therapeutic advantages such as target-specific drug delivery, enhanced bioavailability, biodegradability, and minimal off-target effects. Hybrid nanomaterials as a formulation of anticancer drugs with gold nanoparticles (AuNPs) have adequately proven efficacious in controlled release as well as disintegration into ultrasmall nanoparticles dragging the drug to penetrate deep into tumor tissues and consequently getting cleared from the body. In this study, to achieve better antitumor responses, we engineered self-assembled organic nanoparticles of potent anticancer compound BZ6 (BZ6-ONPs), BZ6-gold nanoparticle conjugates (BZ6-AuNPs), and organic-inorganic nanohybrids involving amalgamation of AuNPs with BZ6-ONPs (AuNPs@BZ6-ONPs) and comparatively analyzed their physicochemical as well as biological activities. The epithelial-mesenchymal transition (EMT) is a critical biological event that facilitates metastatic spread of cancer cells and contributes to chemoresistance. AuNPs@BZ6-ONPs consistently suppressed EMT characteristics including invasion, cell scattering, and migration abilities of aggressive breast cancer (MDA-MB-231) and pancreatic adenocarcinoma (PANC-1) cells much more efficiently than BZ6-ONPs and BZ6-AuNPs. Western blotting and immunocytochemistry analysis unveiled that the nanohybrids downregulated expression of the key mesenchymal markers NF-κβ p65, Twist-1, vimentin, and MMP-2, meanwhile augmenting epithelial marker E-cadherin and tumor suppressor Par-4. The in vivo syngenic mouse tumor model demonstrated remarkable reduction of tumor growth (84.3%) and metastatic lung nodules (66.1%) following 14 days of treatment without any adverse effects. Finally, the facile and ecofriendly method of synthesis of AuNPs@BZ6-ONPs demonstrating promising antitumor/antimetastatic efficacies suggests its therapeutic implication for the treatment of advanced cancers.

Phytochemical-Based Nanomedicine for Advanced Cancer Theranostics: Perspectives on Clinical Trials to Clinical Use.

In the current chapter, a new strategic compilation of phytochemicals with potent antitumor properties has been addressed, most importantly focusing on cell cycle arrest and apoptotic signaling mechanism. A promising approach in tumor prevention is to eliminate cancer cells preferably via cell cycle arrest and programmed cell death with lesser harm to neighboring normal cells. Cancer cells have a survival advantage to escape apoptosis and relentlessly divide to proliferate, gearing up the cell cycle process. Recently, the use of phytochemical-derived conjugated chemotherapeutic agents has increased dramatically owing to its biocompatibility, low cytotoxicity, low resistance, and dynamic physiochemical properties discriminating normal cells in the treatment of various cancer types. For decades, biomedical investigations have targeted cell cycle and apoptotic cell death mechanism as an effective cancer-killing tool for systemically assessing the potential biological interactions of functional phytocompounds compared to its synthetic counterparts during their complete life cycles from entry, biodistribution, cellular/molecular interactions to excretion. Newly emerging nanotechnology application in anticancer drug formulations has revolutionized cancer therapy. Tissue-specific phyto-nanomedicine plays a vital role in advanced cancer diagnostics using liposome, micelle, and nanoparticles as a precise and effective delivery vehicle. This chapter specifically focuses on the therapeutic phytomolecules approved by the Food and Drug Administration (FDA, USA) along with phyto-chemopreventives currently on clinical trials (Phase-I/II/III/IV). Besides, detailed coverage is given to the FDA-approved nanotechnology-based formulations only in the areas of cancer theranostics via cell cycle arrest and apoptotic pathways including present challenges and future perspectives.