1,721,008 research outputs found
Natural Inhibitors of P-glycoprotein in Acute Myeloid Leukemia
Full text linkAcute myeloid leukemia (AML) remains an insidious neoplasm due to the percentage of patients who develop resistance to both classic chemotherapy and emerging drugs. Multidrug resistance (MDR) is a complex process determined by multiple mechanisms, and it is often caused by the overexpression of efflux pumps, the most important of which is P-glycoprotein (P-gp). This mini-review aims to examine the advantages of using natural substances as P-gp inhibitors, focusing on four molecules: phytol, curcumin, lupeol, and heptacosane, and their mechanism of action in AML
Patterns of Innate or Acquired Resistance to Anticancer Drugs: Our Experience to Overcome It
No full textDrug resistance, which is often of a multiple type, can be defined as the ability of cancer cells to obtain resistance to both conventional and novel chemotherapy agents. It remains a major problem to solve in cancer therapy. The mechanisms of resistance are multifactorial, and in our cellular models of acute myeloid leukemia, hepatocellular carcinoma, and triple-negative breast cancer, it involves the NF-κB pathway. In our opinion, multitarget molecules can be considered as privileged compounds capable of attacking and reversing the resistant phenotype. In the phenomena of both innate and acquired drug resistance that we have been studying since 1998 to today and up to 2016 under the guidance of Professor Natale D’Alessandro, more strictly pharmacological factors are certainly involved. These factors include P-glycoprotein and biological factors such as inhibitory proteins; apoptosis; the Raf-1 kinase inhibitor protein, an important tumor suppressor and metastasis inhibitor, which enhances drug-induced apoptosis of cancer cells; and Yin Yang, a transcription factor involved in drug resistance
Potential Therapeutic Applications of MDA-9/Syntenin-NF-κB-RKIP Loop in Human Liver Carcinoma
No full textBackground: Overexpression of MDA-9/Syntenin occurs in multiple human
cancer cell lines and is associated with higher grade of tumor classification,
invasiveness and metastasis. In some cases, its role in cancer biology depends on
relationships between MDA-9/Syntenin and NF-κB.
Objective: This study aims to analyze the presence of a regulation loop like that
between MDA-9/Syntenin - NF-κB - RKIP in human liver carcinoma.
Methods: Transient transfection was performed with siRNA anti-MDA-9/Syntenin.
Expression of different factors was evaluated by Real time-PCR and Western blotting,
while NF-κB activation by TransAM assay. Invasion capacity was analyzed by Matrigel
Invasion Assay and the effects of agents on cell viability were examined by MTS assay.
Results: We have examined basal expression of MDA-9/Syntenin in three cell lines of
human liver carcinoma (HA22T/VGH, Hep3B and HepG2). In all cell lines there was an
inverse relationship between MDA-9/Syntenin and RKIP expression levels, and a
positive correlation between MDA-9/Syntenin expression and NF-κB activation levels. By
silencing with a siRNA anti-MDA-9/Syntenin we observed in all cell lines a very strong
increase of RKIP at mRNA level. Interestingly, in all cell lines, inhibition of MDA-
9/Syntenin expression induced NF-κB downregulation and contemporary a reduction in
invasion ability MMP-2 dependent. Finally, we showed a good additive effect of MDA-
9/Syntenin siRNA when associated with Curcumin or Doxorubicin on cell growth
inhibition.
Conclusion: Our data confirm the key role of MDA-9/Syntenin in HCC biology. The
presence of a regulation loop among MDA-9/Syntenin, NF-κB and RKIP provide new
pharmacological approaches
Phytol and heptacosane: the two major components of Euphorbia intisy essential oil with biological activities in drug resistant leukemia cell.
Full text linkMultidrug resistance has always been a great problem to successfully treat diseases as cancer. Some natural compounds as Essential oils (EOs) are characterized by multiple pharmacological activities including those anticancer. We have previously observed that Euphorbia intisy (Euphorbiaceae) essential oil showed antitumor effects on an acute myeloid leukemia cell line HL-60, and on its MDR variant HL-60R, affecting two different targets: NF-κB pathway and P-gp function. On the contrary of many toxic P-gp inhibitors like verapamil, EO has a low effect on cell death, however, the phytocomplex has the ability to be multitarget due to the presence of numerous substances that synergize, but being extracted from the plant, it is difficult to reproduce. For this reason, we identified the EO compounds to which the mechanism of action could be ascribed: phytol (terpene) and heptacosane (hydrocarbon). Phytol caused a strong decrease of NF-κB activity and consequently of its targets expression. Heptacosane and phytol seem to behave like verapamil on P-gp function, promoting an intracellular accumulation of doxorubicin. These results highlighted the idea that these major components of E. intisy EOs can act as adjuvant in drug resistant diseases
Antitumor Effect of Glandora rosmarinifolia (Boraginaceae) Essential Oil through Inhibition of the Activity of the Topo II Enzyme in Acute Myeloid Leukemia
Full text linkIt was previously shown that the antitumor and cytotoxic activity of the essential oil (EO) extracted from the aerial parts of Glandora rosmarinifolia appears to involve a pro-oxidant mechanism in hepatocellular carcinoma (HCC) and in triple-negative breast cancer (TNBC) cell lines. Its most abundant compound is a hydroxy-methyl-naphthoquinone isomer. Important pharmacological activities, such as antitumor, antibacterial, antifungal, antiviral and antiparasitic activities, are attributed to naphthoquinones, probably due to their pro-oxidant or electrophilic potential; for some naphthoquinones, a mechanism of action of topoisomerase inhibition has been reported, in which they appear to act both as catalytic inhibitors and as topoisomerase II poisons. Our aim was to evaluate the cytotoxic activity of the essential oil on an acute myeloid leukemia cell line HL-60 and on its multidrug-resistant (MDR) variant HL-60R and verify its ability to interfere with topoisomerase II activity. MTS assay showed that G. rosmarinifolia EO induced a decrease in tumor cell viability equivalent in the two cell lines; this antitumor effect could depend on the pro-oxidant activity of EO in both cell lines. Furthermore, G. rosmarinifolia EO reduced the activity of Topo II in the nuclear extracts of HL-60 and HL-60R cells, as inferred from the inability to convert the kinetoplast DNA into the decatenated form and then not inducing linear kDNA. Confirming this result, flow cytometric analysis proved that EO induced a G(0)-G(1) phase arrest, with cell reduction in the S-phase. In addition, the combination of EO with etoposide showed a good potentiation effect in terms of cytotoxicity in both cell lines. Our results highlight the antitumor activity of EO in the HL-60 cell line and its MDR variant with a peculiar mechanism as a Topo II modulator. Unlike etoposide, EO does not cause stabilization of a covalent Topo II-DNA intermediate but acts as a catalytic inhibitor. These data make G. rosmarinifolia EO a potential anticancer drug candidate due to its cytotoxic action, which is not affected by multidrug resistance
Cytotoxicity of oleanolic and ursolic acid derivatives toward hepatocellular carcinoma and evaluation of NF-κB involvement
No full textOleanolic and ursolic acids are two ubiquitous isomeric triterpene phytochemicals known for their anticancer
activity. A set of derivatives of the two compounds with a modified oxidation state and lipophylicity at C-3 and
C-28 positions, were prepared and tested as anticancer agents versus the lines HepG2, Hep3B and HA22T/VGH
of hepatocarcinoma, a strongly aggressive tumor that is not responsive toward the standard therapies. New
derivatives containing a three carbons side chain on the C-3 position were synthetized in both stereoisomeric
forms by the Barbier-Grignard procedure and three of them were found to be active toward all of the three
targets. The implication of the transcriptional nuclear factor NF−κB in the mechanism of action was assessed for
the more active compounds in the set, as hepatocellular carcinoma (HCC) cyto-types are known to overexpress
NF−κB
Targeting Multiple Myeloma with natural polyphenols
Full text linkMultiple myeloma (MM) is still an incurable hematologic malignancy. Although new therapeutic strategies have been developed to target different pathways in malignant cells, such as proliferation, differentiation, and apoptosis, better survival rates have also been achieved by the introduction of autologous stem cell transplantation (ASCT). Hematopoietic stem cell transplantation and novel targeted agents, such as proteasome inhibitors, monoclonal antibodies, immunomodulatory drugs, check-point inhibitors and epigenetic modulators, have significantly achieved long remission time and increased survival rates. However, most patients relapse, develop resistance, and eventually die because of refractorydisease. All these issues highlight the need to investigate newer therapeutic targets to improvepatient outcomes. Natural products play an important role in anti-tumor drug discovery, for this reason,in the investigation of novel natural anti-MM agents, we focused on natural polyphenols. Moreover, plant extracts show no or low toxicity towards normal cells and some of them have also a favorable pharmacokinetic profile. The biological activities of plant extracts are mainly due to their content in polyphenols, flavonoids, and terpenoids. Numerous studies showed that polyphenols, generally recognized as antioxidants, possess anticancer and pro-apoptosis properties. Other studies reported the potential clinical applications of flavonoids for their well-known protective and therapeutic effects against cancer, cardiovascular, and neurodegenerative diseases. The combination of plant extracts with anti-cancer drugs may offer a relevant advantage for therapeutic efficacy by sensitizing malignant cells to drugs and overcoming drug-induced resistance in cancer. For all these reasons, a significant number of polyphenolic compounds isolated from plants are still used nowadays in cancer clinical practice in combination with other drugs, also against hematologic malignancies
Vesicle-Transported Multidrug Resistance as a Possible Therapeutic Target of Natural Compounds
Full text linkBackground/Objectives: A key role of extracellular vesicles (EVs) is mediating both cell–cell and cell–stroma communication in pathological/physiological conditions. EVs from resistant tumor cells can transport different molecules like P-glycoprotein (P-gp), acting as a shuttle between donor and recipient cells, resulting in a phenotypic change. The aim of our work was to isolate, characterize, and inhibit the release of EVs in two multidrug resistance (MDR) cancer models: MCF-7R (breast cancer cell line) and HL-60R (acute myeloid leukemia cell line). Methods: The existence of P-gp in EVs from MDR cells was confirmed by Western blotting assays. The characterization of EVs was carried out by evaluating the size using NTA and the presence of specific markers such as CD63, Hsp70 and Syntenin. The ability of HL-60R and MCF-7R to perform horizontal transfer of P-gp via EVs to sensitive cells was assessed using three different methods. The acquisition of resistance and its inhibition in recipient cells was confirmed by MTS 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) assay. Results: Our data showed that cell lines (MDR) release P-gp-loaded EVs, unlike sensitive cells. The acquisition of resistance determined by the incorporation of P-gp into the membrane of sensitive cells was confirmed by the reduced cytotoxic activity of doxorubicin. Natural compounds such as curcumin, lupeol, and heptacosane can block vesicular transfer and restore the sensitivity of HL-60 and MCF-7 cells. Conclusions: Our study demonstrates that natural inhibitors able to reverse this mechanism may represent a new therapeutic strategy to limit the propagation of the resistant phenotype
In Vitro Modulation of P-Glycoprotein Activity by Euphorbia intisy Essential Oil on Acute Myeloid Leukemia Cell Line HL-60R
Full text linkEuphorbia species have a large spectrum of traditional medicinal uses. We tested the biological activities of the essential oil (EO) of Euphorbia intisy Drake in an acquired multidrug resistance leukemia model to assess whether the EO obtained by hydrodistillation of stems was able to reverse the resistant phenotype. HL-60R cell lines are characterized by the overexpression of P-glycoprotein (P-gp), inhibitors of apoptosis proteins (IAPs) and constitutive expression of NF-κB. EO chemical composition was determined by GC/MS analysis; cytotoxic activity of EO by MTS assay alone or in combination with doxorubicin; pro-apoptotic effect and doxorubicin accumulation were analyzed by flow cytometry; P-gp ATPase activity was measured by P-gp-GloTM assay systems kit. The ability to inhibit NF-κB and its target genes was also assessed. E. intisy EO exhibited a comparable cytotoxic effect and ability to block P-gp in both the HL-60 and its MDR variant HL-60R. In addition, EO suppressed P-gp protein expression and significantly downregulated MDR1 mRNA level, as well as some IAPs proteins, probably through the inhibition of NF-κB. Our results suggest that E. intisy EO could reverse P-gp-mediated drug resistance in tumor cells acting as a chemosensitizing agent
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