Additional considerations in cancer cell radioresistance, integrin αvß3 and thyroid hormones.

BACKGROUND: The existence of a functional relationship between a certain thyroid hormone analogue and cancer cell radioresistance has been shown by Leith and coworkers. The hormone analogue with relevance to malignant cells' radioresistance is tetraiodothyroacetic acid (tetrac). Tetrac is the deaminated derivative of L-thyroxine (T4), the principal product of the thyroid gland. Preclinical studies demonstrated that tetrac and chemically modified tetrac (CMT), e.g. a fluorobenzyl-conjugated tetrac analogue, restores radiosensitivity in certain radioresistant tumor cells. Due to their molecular, physico-chemical, and biological properties, actions of CMT analogues are believed to be initiated at the thyroid hormone analogue receptor site on plasma membrane integrin αvß3. OBJECTIVE: To explore possible molecular mechanisms of the potentially therapeutically beneficial effect of CMT on cancer cells' sensitivity to radiation, we analyzed actions of CMT analogues on expression of selected sets of genes that have been previously implicated in radioresistance of malignant cells. DISCUSSION AND CONCLUSIONS: In the current study, we report that genome-wide gene expression profiling analysis of human glioblastoma (GBM) and acute myelocytic leukemia (AML) cell lines exposed in vitro to noncytotoxic doses of CMT has identified decreased expression of discrete trios of genes each of which was previously linked to cancer cells' radioresistance. Following the CMT treatment in AML cells, expression of PARP9, PARP15 and STAT3 genes was significantly reduced, while in GBM cells, expression of PRKDC, EGFR and CCNDI was significantly decreased by the drug. Notably, a broader spectrum of genes implicated in cancer cells' radioresistance was observed in primary patient-derived GBM cells after the CMT treatment. Extensive additional experimental and clinical studies are indicated, including analyses of individual patient tumor genomics and of an array of different tumor types to define the sub-sets of tumors manifesting radioresistance in which tetrac-based agents may be expected to enhance therapeutic effects of radiation.

RETRACTED: Godugu et al. Anti-Cancer Activities of Thyrointegrin αvß3 Antagonist Mono- and Bis-Triazole Tetraiodothyroacetic Acid Conjugated via Polyethylene Glycols in Glioblastoma. Cancers 2021, 13, 2780.

The journal retracts the article, "Anti-Cancer Activities of Thyrointegrin αvß3 Antagonist Mono- and Bis-Triazole Tetraiodothyroacetic Acid Conjugated via Polyethylene Glycols in Glioblastoma" [...].

A comprehensive review on lipid nanocarrier systems for cancer treatment: fabrication, future prospects and clinical trials.

Over the last few decades, cancer has been considered a clinical challenge, being among the leading causes of mortality all over the world. Although many treatment approaches have been developed for cancer, chemotherapy is still the most utilized in the clinical setting. However, the available chemotherapeutics-based treatments have several caveats including their lack of specificity, adverse effects as well as cancer relapse and metastasis which mainly explains the low survival rate of patients. Lipid nanoparticles (LNPs) have been utilized as promising nanocarrier systems for chemotherapeutics to overcome the challenges of the currently applied therapeutic strategies for cancer treatment. Loading chemotherapeutic agent(s) into LNPs improves drug delivery at different aspects including specific targeting of tumours, and enhancing the bioavailability of drugs at the tumour site through selective release of their payload, thus reducing their undesired side effects on healthy cells. This review article delineates an overview of the clinical challenges in many cancer treatments as well as depicts the role of LNPs in achieving optimal therapeutic outcomes. Moreover, the review contains a comprehensive description of the many LNPs categories used as nanocarriers in cancer treatment to date, as well as the potential of LNPs for future applications in other areas of medicine and research.

What is thyroid function in your just-diagnosed cancer patient?

The principal hormonal product of the thyroid gland, L-thyroxine (T4), is a prohormone for 3,3',5-triiodo-L-thyronine, T3, the major ligand of nuclear thyroid hormone receptors (TRs). At a cell surface thyroid hormone analogue receptor on cancer cell and endothelial cell plasma membrane integrin αvß3, however, T4 at physiological concentrations is biologically active and is the major ligand. At this site in solid tumor cells, T4 nongenomically initiates cell proliferation, is anti-apoptotic by multiple mechanisms, supports radioresistance and enhances cancer-related angiogenesis. In contrast, hypothyroidism has been reported clinically to slow tumor growth. At physiological levels, T3 is not biologically active at the integrin and maintenance of euthyroidism with T3 in cancer patients may be associated with slowed tumor proliferation. Against this background, we raise the possibility that host serum T4 levels that are spontaneously in the upper tertile or quartile of the normal range in cancer patients may be a factor that contributes to aggressive tumor behavior. Recent observations on tumor metastasis and tumor-associated propensity for thrombosis due to T4 also justify clinical statistical analysis for a relationship to upper tertile hormone levels. That reverse T3 (rT3) may stimulate tumor growth has recently been reported and thus the utility of adding this measurement to thyroid function testing in cancer patients requires assessment. In summary, T4 at physiological concentrations promotes tumor cell division and aggressiveness and euthyroid hypothyroxinemia arrests clinically advanced solid tumors. These findings support the clinical possibility that T4 levels in the upper tertile of the normal range require examination as a tumor supporting factor.

Discovery of novel thyrointegrin αvß3 antagonist fb-PMT (NP751) in the management of human glioblastoma multiforme.

Background: Thyrointegrin αvß3 receptors are unique molecular cancer therapeutic targets because of their overexpression on cancer and rapidly dividing blood vessel cells compared and quiescent on normal cells. A macromolecule, TriAzole Tetraiodothyroacetic acid (TAT) conjugated to polyethylene glycol with a lipophilic 4-fluorobenyl group (fb-PMT and NP751), interacts with high affinity (0.21 nM) and specificity with the thyrointegrin αvß3 receptors on the cell surface without nuclear translocation in contrast to the non-polymer conjugated TAT. Methods: The following in vitro assays were carried out to evaluate NP751 including binding affinity to different integrins, transthyretin (TTR)-binding affinity, glioblastoma multiforme (GBM) cell adhesion, proliferation assays, nuclear translocations, chorioallantoic membrane model of angiogenesis, and microarray for molecular mechanisms. Additionally, in vivo studies were carried out to evaluate the anticancer efficacy of NP751, its biodistribution, and brain GBM tumor versus plasma levels kinetics. Results: NP751 demonstrated a broad spectrum of antiangiogenesis and anticancer efficacy in experimental models of angiogenesis and xenografts of human GBM cells. Tumor growth and cancer cells' viability were markedly decreased (by > 90%; P < .001) in fb-PMT-treated U87-luc or 3 different primary human GBM xenograft-bearing mice based on tumor in vivo imaging system (IVIS) imaging and histopathological examination, without relapse upon treatment discontinuation. Additionally, it effectively transports across the blood-brain barrier via its high-affinity binding to plasma TTR with high retention in brain tumors. NP751-induced effects on gene expression support the model of molecular interference at multiple key pathways essential for GBM tumor progression and vascularization. Conclusions: fb-PMT is a potent thyrointegrin αvß3 antagonist with potential impact on GBM tumor progression.

Preclinical assessment of drug-drug interaction of fb-PMT, a novel anti-cancer thyrointegrin αvß3 antagonist.

The objective of the current study was to identify potential drug-drug interactions (DDIs) with the drug candidate fb-PMT, a novel anticancer thyrointegrin αvß3 antagonist. This was accomplished by using several in vitro assays to study interactions of fb-PMT with both cytochrome P450 (CYP) enzymes and drug transporters, two common mechanisms leading to adverse drug effects. In vitro experiments showed that fb-PMT exhibited weak reversible inhibition of CYP2C19 and CYP3A4. In addition, fb-PMT did not show time-dependent inhibition with any of the seven CYP isoforms tested, including 1A2, 2B6, 2C8, 2C9, 2C19, 2D6, and 3A4. Human liver microsomal incubations demonstrated that fb-PMT is stable. Potential transporter-mediated DDIs with fb-PMT were assessed with two ATP binding cassette (ABC) family transporters (P-glycoprotein and breast cancer resistance protein) using Caco2 cells and seven solute carrier family (SLC) transporters (organic cation transporter OCT2, organic anion transporters OAT1 and OAT3, organic anion transporter peptides OATP1B1 and OATP1B3, and the multidrug and toxic extrusion proteins MATE1 and MATE2-K using transfected HEK293 cells). Fb-PMT was not a substrate for any of the nine transporters tested in this study, nor did it inhibit the activity of seven of the transporters tested. However, fb-PMT inhibited the uptake of rosuvastatin by both OATP1B1 and OATP1B3 with half-maximal inhibitory concentrations greater than 3 and less than 10 µM. In summary, data suggest that the systemic administration of fb-PMT is unlikely to lead to DDIs through CYP enzymes or ABC and SLC transporters in humans.

Natural bioactive compounds-doxorubicin combinations targeting topoisomerase II-alpha: Anticancer efficacy and safety.

Cancer is one of the leading causes of death worldwide, so pursuing effective and safe therapeutics for cancer is a key research objective nowadays. Doxorubicin (DOX) is one of the commonly prescribed chemotherapeutic agents that has been used to treat cancer with its antimitotic properties via inhibition of topoisomerase II (TOP2) activity. However, many problems hinder the broad use of DOX in clinical practice, including cardiotoxicity and drug resistance. Research in drug discovery has confirmed that natural bioactive compounds (NBACs) display a wide range of biological activities correlating to anticancer outcomes. The combination of NBACs has been seen to be an ideal candidate that might increase the effectiveness of DOX therapy and decreases its unfavorable adverse consequences. The current review discusses the chemo-modulatory mechanism and the protective effects of combined DOX with NBACs with a binding affinity (pKi) toward TOP2A more than pKi of DOX. This review will also discuss and emphasize the molecular mechanisms to provide a pathway for further studies to reveal other signaling pathways. Taken together, understanding the fundamental mechanisms and implications of combined therapy may provide a practical approach to battling cancer diseases.

Future regenerative medicine developments and their therapeutic applications.

Although the currently available pharmacological assays can cure most pathological disorders, they have limited therapeutic value in relieving certain disorders like myocardial infarct, peripheral vascular disease, amputated limbs, or organ failure (e.g. renal failure). Pilot studies to overcome such problems using regenerative medicine (RM) delivered promising data. Comprehensive investigations of RM in zebrafish or reptilians are necessary for better understanding. However, the precise mechanisms remain poorly understood despite the tremendous amount of data obtained using the zebrafish model investigating the exact mechanisms behind their regenerative capability. Indeed, understanding such mechanisms and their application to humans can save millions of lives from dying due to potentially life-threatening events. Recent studies have launched a revolution in replacing damaged human organs via different approaches in the last few decades. The newly established branch of medicine (known as Regenerative Medicine aims to enhance natural repair mechanisms. This can be done through the application of several advanced broad-spectrum technologies such as organ transplantation, tissue engineering, and application of Scaffolds technology (support vascularization using an extracellular matrix), stem cell therapy, miRNA treatment, development of 3D mini-organs (organoids), and the construction of artificial tissues using nanomedicine and 3D bio-printers. Moreover, in the next few decades, revolutionary approaches in regenerative medicine will be applied based on artificial intelligence and wireless data exchange, soft intelligence biomaterials, nanorobotics, and even living robotics capable of self-repair. The present work presents a comprehensive overview that summarizes the new and future advances in the field of RM.

Correction: Godugu et al. Nanoformulated Ajwa (Phoenix Dactylifera) Bioactive Compounds Improve the Safety of Doxorubicin without Compromising Its Anticancer Efficacy in Breast Cancer. Molecules 2020, 25, 2597.

In the original publication [...].

Pharmacokinetics of fluorobenzyl polyethylene glycol conjugated tetraiodothyroacetic acid (NP751), a novel anticancer thyrointegrin αvß3 antagonist.

We have recently reported on the development of fb-PMT (NP751), a conjugate of the thyroid hormone metabolite tetraiodothyroacetic acid (tetrac) and monodisperse polyethylene glycol 36. It exhibited high affinity for thyrointegrin αvß3 receptor and potent anti-angiogenic and anticancer activity in vivo. The objective of the current study is to determine the pharmacokinetics (PK) of fb-PMT in experimental animals, such as mice, rats, and monkeys. NP751 was quantified using a propylene diamine-modified tetraiodothyroacetic acid (DAT) as an internal standard. The limit of quantification (LOQ) for fb-PMT was 1.5 ng/µL and the recovery efficiency was 93.9% with the developed method. The peak plasma concentration (Cmax) and the area under the curve (AUC) results at different doses in mice, rats and monkeys suggest that pharmacokinetics of NP751 is dose-dependent within the dose ranges administered. Results indicate that NP751 has comparable PK parameters that provides enough exposure as a molecularly tumor targeted molecule in multiple species and is a promising anticancer therapeutic.

Correction: Godugu et al. Anti-Cancer Activities of Thyrointegrin αvß3 Antagonist Mono- and Bis-Triazole Tetraiodothyroacetic Acid Conjugated via Polyethylene Glycols in Glioblastoma. Cancers 2021, 13, 2780.

In the original publication [...].

Antitumor/anti-angiogenesis efficacy of epigallocatechin gallate nanoformulated with antioxidant in melanoma.

Aim: Epigallocatechin gallate (EGCG) derived from green tea has poor stability; therefore, to enhance its bioavailability and anticancer efficiency, we synthesized three different nanoformulations. We hypothesized that these three nanoformulations of EGCG (nano-EGCG) would enhance EGCG's stability and improve its anticancer and antiangiogenic activity against melanoma compared with free EGCG. Methods: We prepared nano-EGCG using a copolymerization method with the UV blocker ZnO and the antioxidants lycopene and olive oil. Results: The different nano-EGCG formulation exhibited improved EGCG stability and greater suppression of melanoma growth than free EGCG. Nanoformulation preparation methods efficiently prevented the loss of EGCG activity and are a favorable approach for the treatment of melanoma. Conclusion: Nano-EGCG formulations had enhanced stability and produced greater suppression of melanoma tumor growth and angiogenesis compared with free EGCG.

Colony stimulating factors for prophylaxis of chemotherapy-induced neutropenia in children.

INTRODUCTION: Febrile neutropenia (FN) is one of the complications of chemotherapy that can increase the risk of infection and mortality. Granulocyte colony-stimulating factors (G-CSFs) are used in practice to prevent and treat episodes of neutropenia. The use of G-CSFs in children with cancer has not been studied much for primary prophylaxis of FN. AREAS COVERED: Current data suggest that G-CSFs have a similar pharmacokinetic profile in children and adults. Clinical trials published from 2002 to 2021 using G-CSFs in pediatric cancer patients were reviewed. All evaluated clinical trials used a dosage of 5 mcg/kg of filgrastim daily until neutrophil recovery or a single dose of 100 mcg/kg pegfilgrastim. Filgrastim demonstrated the benefit in decreasing the duration of fever, hospital stay, and antibiotic use in high-risk neuroblastoma patients. Pegfilgrastim showed similar efficacy in reducing the occurrence of FN and infections, with bone pain as an adverse effect. EXPERT OPINION: Filgrastim 5 mcg/kg/day or pegfilgrastim 100 mcg/kg single dose is appropriate when given at least 24 hours or after the chemotherapy in pediatric patients who weigh 45 kg or more. More prospective randomized trials are necessary to further investigate the efficacy and safety of G-CSFs in children with different types of cancer.

Mitochondria-targeted alginate/triphenylphosphonium-grafted-chitosan for treatment of hepatocellular carcinoma.

Mitochondrial targeting of anticancer drugs can effectively eradicate chemotherapy-refractory cells through different mechanisms. This work presents the rational designing of mitochondria-targeted core-shell polymeric nanoparticles (NPs) for efficient delivery of doxorubicin (DOX) to the hepatic carcinoma mitochondria. DOX was electrostatically nano-complexed with sodium alginate (SAL) then coated with mitotropic triphenylphosphonium-grafted chitosan (TPP+-g-CS) nanoshell. Polyvinyl alcohol (PVA) was co-solubilized into the TPP+-g-CS solution to enhance the stability of the developed NPs. The optimum NPs formula is composed of TPP+-g-CS (0.05% w/v) coating a DOX-SAL core complex (0.05% w/v), with 0.2% PVA relative to CS (w/w). The optimum NPs attained an entrapment efficiency of 63.33 ± 10.18%; exhibited a spherical shape with particle size of 70-110 nm and a positive surface charge which enhances mitochondrial uptake. FTIR and DSC studies results were indicative of an efficacious poly-complexation. In vitro biological experiments proved that the developed mitotropic NPs exhibited a significantly lower IC50, effectively induced apoptotic cell death and cell cycle arrest. Moreover, the in vivo studies demonstrated an enhanced antitumor bioactivity for the mitotropic NPs along with a reduced biological toxicity profile. In conclusion, this study proposes a promising nanocarrier system for the efficient targeting of DOX to the mitochondria of hepatic tumors.

Curcumin, thymoquinone, and 3, 3'-diindolylmethane combinations attenuate lung and liver cancers progression.

Cancer can develop due to abnormal cell proliferation in any body's cells, so there are over a hundred different types of cancer, each with its distinct behavior and response to treatment. Therefore, many studies have been conducted to slow cancer progression and find effective and safe therapies. Nutraceuticals have great attention for their anticancer potential. Therefore, the current study was conducted to investigate the anticancer effects of curcumin (Cur), thymoquinone (TQ), and 3, 3'-diindolylmethane (DIM) combinations on lung (A549) and liver (HepG2) cancer cell lines' progression. Results showed that triple (Cur + TQ + DIM) and double (Cur + TQ, Cur + DIM, and TQ + DIM) combinations of Cur, TQ, and DIM significantly increased apoptosis with elevation of caspase-3 protein levels. Also, these combinations exhibited significantly decreased cell proliferation, migration, colony formation activities, phosphatidylinositol 3-kinase (PI3K), and protein kinase B (AKT) protein levels with S phase reduction. Triple and double combinations of Cur, TQ, and DIM hindered tumor weight and angiogenesis of A549 and HepG2 implants in the chorioallantoic membrane model. Interestingly, Cur, TQ, and DIM combinations are considered promising for suppressing cancer progression via inhibiting tumor angiogenesis. Further preclinical and clinical investigations are warranted.

Edible Green Solvent for Optimized Catechins Extraction from Green Tea Leaves: Anti-Hypercholesterolemia.

Catechin polyphenols are the major bioactive ingredients in green tea with various human health benefits. Extraction of catechins from green tea (GTE) leaves at optimized standard conditions is still a challenging approach. An optimized, rapid, and economic extraction method is industrially needed. We hypothesized that certain extraction techniques in the presence of natural polymers and antioxidants might improve GTE catechin extraction yield and its biological activity. The effect of microwave (30-60 seconds irradiation in a typical kitchen microwave) assisted extraction (MAE) and ultrasonic assisted extraction (UAE) techniques were evaluated separately and in combination. To study the effect of the extraction solvent, nine edible green solvent combinations were investigated namely water, ascorbic acid, chitosan/ascorbic acid, carboxymethylcellulose /ascorbic acid, methylcellulose /ascorbic acid, chitosan/methylcellulose/ascorbic acid, methylcellulose, chitosan/acetic acid, and ethanol. The amounts of extracted catechins from green tea leaves were quantified with HPLC-UV. Data showed that the use of MAE & UAE technique was the optimal in producing a higher extraction yield of catechins. Chitosan/ascorbic acid was the optimized solvent with high extraction efficiencies of catechins. Studies in high fat diet fed animals demonstrated significant reduction of total cholesterol and LDL-C by GTE after 3 weeks of oral daily administration. In conclusion, efficient extraction, and stabilization of catechins from green tea leaves demonstrated a significant lowering of high fat diet-mediated elevation in blood cholesterol and LDL-C levels.

Three-dimensional (3D) cell culture: a valuable step in advancing treatments for human hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is the fifth most common malignant cancer and the third most frequent cause of tumour-related mortality worldwide. Currently, several surgical and medical therapeutic strategies are available for HCCs; however, the interaction between neoplastic cells and non-neoplastic stromal cells within the tumour microenvironment (TME) results in strong therapeutic resistance of HCCs to conventional treatment. Therefore, the development of novel treatments is urgently needed to improve the survival of patients with HCC. The first step in developing efficient chemotherapeutic drugs is the establishment of an appropriate system for studying complex tumour culture and microenvironment interactions. Three-dimensional (3D) culture model might be a crucial bridge between in vivo and in vitro due to its ability to mimic the naturally complicated in vivo TME compared to conventional two-dimensional (2D) cultures. In this review, we shed light on various established 3D culture models of HCC and their role in the investigation of tumour-TME interactions and HCC-related therapeutic resistance.

Management of Pancreatic Cancer and Its Microenvironment: Potential Impact of Nano-Targeting.

Pancreatic ductal adenocarcinoma (PDAC) is rare and difficult to treat, making it a complicated diagnosis for every patient. These patients have a low survival rate along with a poor quality of life under current pancreatic cancer therapies that adversely affect healthy cells due to the lack of precise drug targeting. Additionally, chemoresistance and radioresistance are other key challenges in PDAC, which might be due in part to the lack of tumor-targeted delivery of sufficient levels of different chemotherapies because of their low therapeutic index. Thus, instead of leaving a trail of off-target damage when killing these cancer cells, it is best to find a way that targets them directly. More seriously, metastatic relapse often occurs after surgery, and therefore, achieving improved outcomes in the management of PDAC in the absence of strategies preventing metastasis is likely to be impossible. Nano-targeting of the tumor and its microenvironment has shown promise for treating various cancers, which might be a promising approach for PDAC. This review updates the advancements in treatment modalities for pancreatic cancer and highlights future directions that warrant further investigation to increase pancreatic patients' overall survival.