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Doxorubicin represents a valuable choice for different cancers, although the severe side effects occurring at the high effective dose limits its clinical use. In the present study, potential strategies to potentiate low-dose doxorubicin efficacy, including a metronomic schedule, characterized by a short and repeated exposure to the anticancer drug, and the combination with the natural chemosensitizing sesquiterpenes β-caryophyllene and β-caryophyllene oxide, were assessed in human hepatoma HepG2 cells. The involvement of P-glycoprotein (P-gp) in the HepG2–chemosensitization to doxorubicin was evaluated. Also, the direct interaction of caryophyllene sesquiterpenes with P-gp was characterized by molecular docking and dynamic simulation studies. A metronomic schedule allowed us to enhance the low-dose doxorubicin cytotoxicity and the combination with caryophyllane sesquiterpenes further potentiated this effect. Also, an increased intracellular accumulation of doxorubicin and rhodamine 123 induced by caryophyllane sesquiterpenes was found, thus suggesting their interference with P-gp function. A lowered expression of P-gp induced by the combinations, with respect to doxorubicin alone, was observed too. Docking studies found that the binding site of caryophyllane sesquiterpene was next to the ATP binding domain of P-gp and that β-caryophyllene possessed the stronger binding affinity and higher inhibition potential calculated by MM-PBSA. Present findings strengthen our hypothesis about the potential chemosensitizing power of caryophyllane sesquiterpenes and suggest that combining a chemosensitizer and a metronomic schedule can represent a suitable strategy to overcome drawbacks of doxorubicin chemotherapy while exploiting its powerful activity. [ABSTRACT FROM AUTHOR]

Introduction: Anticancer chemotherapy often faces the problem of intrinsic or acquired drug refractoriness due in part to efficient mechanisms of defense present or developed, respectively, in cancer cells. Owing to their polarity and/or high molecular weight, many cytostatic agents cannot freely cross the plasma membrane by simple diffusion and hence depend on SLC proteins to enter cancer cells. The downregulation of these transporters and the appearance of either inactivating mutations or aberrant splicing, hamper the possibility of anticancer drugs to interact with their intracellular targets. Areas covered: In addition to specific literature, we have revised Gene database of the NCBI PubMed resources and information publicly available at NIH 'The Cancer Genome Atlas' (TCGA) (update November 2018) to evaluate the relationship between the profile of expression of SLC transporters playing a major role in the transportome and accounting for drug uptake, in healthy and tumor tissue, and their ability to recognize as substrate several antitumor drugs frequently used in the treatment of different types of cancer, which could affect the overall response to chemotherapy based on regimens including these drugs. Expert commentary: Changes in the transportome may affect the overall response to chemotherapy based on drugs taken up by SLC transporters. [ABSTRACT FROM AUTHOR]

Cholangiocarcinoma and hepatocellular carcinoma are primary liver cancers, both representing a growing challenge due to their increasing morbidity and mortality. A “metronomic chemotherapy", consisting of the repeated administration of low and/ or continuous doses of anti-neoplastic drugs, represents an alternative approach to the standard chemotherapy [1]. Numerous natural substances exhibited in vitro chemosensitizing features: in particular, the natural sesquiterpene β-caryophyllene (CRY) has been proved to increase the cytotoxicity of doxorubicin (DOXO) in leukemic cells [2]. Hence, our aim has been to evaluate the ability of CRY to enhance the efficacy of low-dose DOXO in human liver cancer cells, by applying a metronomic protocol. To this end, human liver HepG2 and CCA cells have been used as models of hepatocellular carcinoma and cholangiocarcinoma. The metronomic protocol was based on a 2h low-time exposition to the test substances, followed by 72h incubation for restoring. This scheduling has been applied 3 times and cytotoxicity was measured by MTT assay. Both the substances alone (CRY 1-100 μg/ml; DOXO 1-500 μg/ml) and the combination of DOXO with a nontoxic concentration of CRY were assessed. We found that the repeated treatments with low concentrations produced a significant potentiation (about 30 %) of DOXO cytotoxicity in HepG2. The combination with CRY increased the DOXO activity, reaching a 70 % inhibition of cell viability at 50 μg/ml after 2 repeated treatments. Similar effects were found in CCA, although repeated treatments induced no additional potentiation. These results highlight a possible role of CRY as a chemosensitizing agent for DOXO-based chemotherapy of liver cancer. [ABSTRACT FROM AUTHOR]

A multi-methodological approach was applied to study red sweet peppers ( Capsicum annuum L.) ecotype “Cornetto di Pontecorvo” grown in a greenhouse or in open field. This approach includes morphological analysis, chemical composition determination, and biological activity evaluation of different extracts from pepper fruits. Untargeted analyses, namely NMR spectroscopy and mass spectrometry, allowed the comprehensive pepper metabolite profile of pepper pulp, peel and seeds hydroalcoholic and organic extracts to be determined, showing the presence of sugars, organic acids, amino acids and other secondary metabolites. Targeted analyses, such as HPLC-PDA, HPLC-TLC and spectrophotometric analyses allowed polyphenols, tannins, flavonoids and pigments content to be determined. Samples quality and freshness were verified by the low content of biogenic amines and mycotoxins, as determined using HPLC-FLD and HPLC-MS, respectively. Preliminary biological results demonstrated the ability of the organic extracts to inhibit α-amylase, a key enzyme in the control of glucose metabolism. [ABSTRACT FROM AUTHOR]

Introduction : Chemotherapy remains the only option for advanced cancer patients when other alternatives are not feasible. Nevertheless, the success rate of this type of therapy is often low due to intrinsic or acquired mechanisms of chemoresistance. Among them, drug extrusion from cancer cells through ATP-binding cassette (ABC) proteins plays an important role. ABC pumps are primary active transporters involved in the barrier and secretory functions of many healthy cells. Areas covered : In this review, we have used The Cancer Genome Atlas (TCGA) database to explore the relationship between the expression of the major ABC proteins involved in cancer chemoresistance in the most common types of cancer, and the drugs used in the treatment of these tumors that are substrates of these pumps. Expert opinion : From unicellular organisms to humans, several ABC proteins play a major role in detoxification processes. Cancer cells exploit this ability to protect themselves from cytostatic drugs. Among the ABC pumps, MDR1, MRPs and BCRP are able to export many antitumor drugs and are expressed in several types of cancer, and further up-regulated during treatment. This event results in the enhanced ability of tumor cells to reduce intracellular drug concentrations and hence the pharmacological effect of chemotherapy.

The natural sesquiterpene β-caryophyllene (CRY) has been highlighted to possess interesting pharmacological potentials, particularly due to its chemopreventive and analgesic properties. However, the poor solubility of this sesquiterpene in aqueous fluids can hinder its uptake into cells, resulting in inconstant responses of biological systems, thus limiting its application. Therefore, identifying a suitable pharmaceutical form for increasing CRY bioavailability represents an important requirement for exploiting its pharmacological potential. In the present study, the ability of soybean phosphatidylcholine (SPC) liposomes to improve bioavailability and absorption of CRY in cancer cells has been evaluated. Liposomal formulations of CRY, differing for lamellarity (i.e., unilamellar and multilamellar vesicles or ULV and MLV) and for the drug loading (i.e., 1:0.1, 1:0.3 and 1:0.5 mol/mol between SPC and CRY) were designed with the aim of maximizing CRY amount in the liposome bilayer, while avoiding its leakage during storage. The low-loaded formulations significantly potentiated the antiproliferative activity of CRY in both HepG2 and MDA-MB-468 cells, reaching a maximum IC 50 lowering (from two to five folds) with 1:0.3 and 1:0.1 SPC/CRY MLV. Conversely, increasing liposome drug-loading reduced the ability for CRY release, likely due to a possible interaction between SPC and CRY that affects the membrane properties, as confirmed by physical measures.