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European Journal of Pharmacology Jun 2024Cancer often involves the overactivation of RAS/RAF/MEK/ERK (MAPK) and PI3K-Akt-mTOR pathways due to mutations in genes like RAS, RAF, PTEN, and PIK3CA. Various... (Review)
Review
Cancer often involves the overactivation of RAS/RAF/MEK/ERK (MAPK) and PI3K-Akt-mTOR pathways due to mutations in genes like RAS, RAF, PTEN, and PIK3CA. Various strategies are employed to address the overactivation of these pathways, among which targeted therapy emerges as a promising approach. Directly targeting specific proteins, leads to encouraging results in cancer treatment. For instance, RTK inhibitors such as imatinib and afatinib selectively target these receptors, hindering ligand binding and reducing signaling initiation. These inhibitors have shown potent efficacy against Non-Small Cell Lung Cancer. Other inhibitors, like lonafarnib targeting Farnesyltransferase and GGTI 2418 targeting geranylgeranyl Transferase, disrupt post-translational modifications of proteins. Additionally, inhibition of proteins like SOS, SH2 domain, and Ras demonstrate promising anti-tumor activity both in vivo and in vitro. Targeting downstream components with RAF inhibitors such as vemurafenib, dabrafenib, and sorafenib, along with MEK inhibitors like trametinib and binimetinib, has shown promising outcomes in treating cancers with BRAF-V600E mutations, including myeloma, colorectal, and thyroid cancers. Furthermore, inhibitors of PI3K (e.g., apitolisib, copanlisib), AKT (e.g., ipatasertib, perifosine), and mTOR (e.g., sirolimus, temsirolimus) exhibit promising efficacy against various cancers such as Invasive Breast Cancer, Lymphoma, Neoplasms, and hematological malignancies. This review offers an overview of small molecule inhibitors targeting specific proteins within the RAS upstream and downstream signaling pathways in cancer.
PubMed: 38866361
DOI: 10.1016/j.ejphar.2024.176727 -
Pharmacological Research Sep 2022The serine/threonine kinase Akt is a major player in the phosphoinositide 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) signaling pathway, and its modulation... (Review)
Review
The serine/threonine kinase Akt is a major player in the phosphoinositide 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) signaling pathway, and its modulation impacts multiple cellular processes such as growth, proliferation, and survival. Several abnormalities in this pathway have been documented over the years, and these alterations were shown to have great implications in tumorigenesis and resistance to chemotherapy. Thus, multiple Akt inhibitors have been developed and tested in adult tumors, and some of them are currently undergoing phase I, II, and III clinical trials for distinct cancers that arise during adulthood. Despite that, the impact of these inhibitors is still not fully understood in pediatric tumors, and Akt-specific targeting seems to be a promising approach to treat children affected by cancers. This review summarizes recent available evidence of Akt inhibitors in pediatric cancers, from both preclinical and clinical studies. In short, we demonstrate the impact that Akt inhibition provides in tumorigenesis, and we suggest targeting the PI3K/Akt/mTOR signaling pathway, alone or in combination with other inhibitors, is a feasible tool to achieve better outcomes in pediatric tumors.
Topics: Adult; Carcinogenesis; Child; Humans; Neoplasms; Phosphatidylinositol 3-Kinases; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-akt; Sirolimus; TOR Serine-Threonine Kinases
PubMed: 35987481
DOI: 10.1016/j.phrs.2022.106403 -
World Journal of Clinical Oncology Oct 2016The Akt signal transduction pathway controls most hallmarks of cancer. Activation of the Akt cascade promotes a malignant phenotype and is also widely implicated in drug... (Review)
Review
The Akt signal transduction pathway controls most hallmarks of cancer. Activation of the Akt cascade promotes a malignant phenotype and is also widely implicated in drug resistance. Therefore, the modulation of Akt activity is regarded as an attractive strategy to enhance the efficacy of cancer therapy and irradiation. This pathway consists of phosphatidylinositol 3 kinase (PI3K), mammalian target of rapamycin, and the transforming serine-threonine kinase Akt protein isoforms, also known as protein kinase B. DNA-targeted agents, such as platinum agents, taxanes, and antimetabolites, as well as radiation have had a significant impact on cancer treatment by affecting DNA replication, which is aberrantly activated in malignancies. However, the caveat is that they may also trigger the activation of repairing mechanisms, such as upstream and downstream cascade of Akt survival pathway. Thus, each target can theoretically be inhibited in view of improving the potency of conventional treatment. Akt inhibitors, ., MK-2206 and perifosine, or PI3K modulators, ., LY294002 and Wortmannin, have shown some promising results in favor of sensitizing the cancer cells to the therapy and , which have provided the rationale for incorporation of these novel agents into multimodality treatment of different malignancies. Nevertheless, despite the acceptable safety profile of some of these agents in the clinical studies, with regard to the efficacy, the results are still too preliminary. Hence, we need to wait for the upcoming data from the ongoing trials before utilizing them into the standard care of cancer patients.
PubMed: 27777878
DOI: 10.5306/wjco.v7.i5.352 -
Journal of Chemotherapy (Florence,... Oct 2021Colorectal cancer is one of the most common cancers throughout the world, and no definitive cure has ever been found. Perhaps a new insight into the effectiveness of... (Review)
Review
Colorectal cancer is one of the most common cancers throughout the world, and no definitive cure has ever been found. Perhaps a new insight into the effectiveness of chemotherapy drugs could help better treat patients. Targeted therapies have significantly improved the median overall survival of colorectal cancer patients. One of the standard chemotherapy regimens used for colorectal cancer is capecitabine, which is important in monotherapy and combination therapies. Capecitabine, with other chemotherapeutic agents (irinotecan, oxaliplatin, perifosine, 17-allylamino-17-demethoxygeldanamycin, aspirin, celecoxib, statins, quinacrine, inositol hexaphosphate and inositol, cystine/theanine, curcumin, and isorhamnetin), and biological ones (antibodies) plays an important role in the inhibition of some signaling pathways, increasing survival, reducing tumor growth and side effects of capecitabine. However, some drugs, such as proton pump inhibitors, are negatively related to capecitabine; therefore, the purpose of this work is to review and discuss the performance of capecitabine combination therapies in colorectal cancer.
Topics: Antineoplastic Combined Chemotherapy Protocols; Capecitabine; Chemokines; Colorectal Neoplasms; DNA Methylation; ErbB Receptors; Humans; Proto-Oncogene Proteins B-raf; Proto-Oncogene Proteins p21(ras); Proton Pump Inhibitors; Receptor, ErbB-2; Signal Transduction
PubMed: 34019782
DOI: 10.1080/1120009X.2021.1920247 -
Frontiers in Pharmacology 2020Autophagy is a highly conserved multistep process and functions as passage for degrading and recycling protein aggregates and defective organelles in eukaryotic cells.... (Review)
Review
Autophagy is a highly conserved multistep process and functions as passage for degrading and recycling protein aggregates and defective organelles in eukaryotic cells. Based on the nature of these materials, their size and degradation rate, four types of autophagy have been described, chaperone mediated autophagy, microautophagy, macroautophagy, and selective autophagy. One of the major regulators of this process is mTOR, which inhibits the downstream pathway of autophagy following the activation of its complex 1 (mTORC1). Alkylphosphocholine (APC) derivatives represent a novel class of antineoplastic agents that inhibit the serine-threonine kinase Akt ( protein kinase B), which mediates cell survival and cause cell cycle arrest. They induce autophagy through inhibition of the Akt/mTOR cascade. They interfere with phospholipid turnover and thus modify signaling chains, which start from the cell membrane and modulate PI3K/Akt/mTOR, Ras-Raf-MAPK/ERK and SAPK/JNK pathways. APCs include miltefosine, perifosine, and erufosine, which represent the first-, second- and third generation of this class, respectively. In a high fraction of human cancers, constitutively active oncoprotein Akt1 suppresses autophagy and . mTOR is a down-stream target for Akt, the activation of which suppresses autophagy. However, treatment with APC derivatives will lead to dephosphorylation (hence deactivation) of mTOR and thus induces autophagy. Autophagy is a double-edged sword and may result in chemotherapeutic resistance as well as cancer cell death when apoptotic pathways are inactive. APCs display differential autophagy induction capabilities in different cancer cell types. Therefore, autophagy-dependent cellular responses need to be well understood in order to improve the chemotherapeutic outcome.
PubMed: 32410999
DOI: 10.3389/fphar.2020.00547 -
Frontiers in Oncology 2020Colorectal cancer (CRC) is a disease with constantly increasing incidence and high mortality. The treatment efficacy could be curtailed by drug resistance resulting from...
Colorectal cancer (CRC) is a disease with constantly increasing incidence and high mortality. The treatment efficacy could be curtailed by drug resistance resulting from poor drug penetration into tumor tissue and the tumor-specific microenvironment, such as hypoxia and acidosis. Furthermore, CRC tumors can be exposed to different pH depending on the position in the intestinal tract. CRC tumors often share upregulation of the Akt signaling pathway. In this study, we investigated the role of external pH in control of cytotoxicity of perifosine, the Akt signaling pathway inhibitor, to CRC cells using 2D and 3D tumor models. In 3D settings, we employed an innovative strategy for simultaneous detection of spatial drug distribution and biological markers of proliferation/apoptosis using a combination of mass spectrometry imaging and immunohistochemistry. In 3D conditions, low and heterogeneous penetration of perifosine into the inner parts of the spheroids was observed. The depth of penetration depended on the treatment duration but not on the external pH. However, pH alteration in the tumor microenvironment affected the distribution of proliferation- and apoptosis-specific markers in the perifosine-treated spheroid. Accurate co-registration of perifosine distribution and biological response in the same spheroid section revealed dynamic changes in apoptotic and proliferative markers occurring not only in the perifosine-exposed cells, but also in the perifosine-free regions. Cytotoxicity of perifosine to both 2D and 3D cultures decreased in an acidic environment below pH 6.7. External pH affects cytotoxicity of the other Akt inhibitor, MK-2206, in a similar way. Our innovative approach for accurate determination of drug efficiency in 3D tumor tissue revealed that cytotoxicity of Akt inhibitors to CRC cells is strongly dependent on pH of the tumor microenvironment. Therefore, the effect of pH should be considered during the design and pre-clinical/clinical testing of the Akt-targeted cancer therapy.
PubMed: 33344237
DOI: 10.3389/fonc.2020.581365 -
Biochemical Pharmacology Jul 2015Perifosine exerts an antiproliferative effect on HepG2 and U-87 MG cells and also interferes with the transport of cholesterol from the plasma membrane to the...
Perifosine exerts an antiproliferative effect on HepG2 and U-87 MG cells and also interferes with the transport of cholesterol from the plasma membrane to the endoplasmic reticulum (ER). Recently we demonstrated that exposure of U-87 MG cells to perifosine causes an accumulation of autophagosomes. We have now expanded the study to establish the molecular mechanism by which perifosine interferes with the autophagic process. Using transmission electron microscopy, we report that the treatment of HepG2 and U-87 MG cells with perifosine causes an intense cytoplasmic vacuolization identified as autophagic vesicles. The accumulation of autophagosomes induced by perifosine is due to a blockage of the autophagic flux, thereby affecting cell proliferation. Perifosine also provokes a differential ER stress response in the HepG2 and U-87 MG cell lines. We have also demonstrated a relationship between the deregulation of cholesterol transport and the inhibition of the autophagic flux prompted by perifosine. Thus our findings clearly demonstrate that perifosine impairs the autophagic flux in HepG2 and U-87 MG cells, which is related to defects in intracellular cholesterol transport. Our study is relevant for anticancer therapy because tumour cells exhibit autophagy as a pro-survival mechanism. Further research to identify the precise mechanisms of autophagy maturation and the role of cholesterol may provide new insights into the antiproliferative action of perifosine.
Topics: Autophagy; Brain Neoplasms; Cell Line, Tumor; Cholesterol; Glioblastoma; Hepatoblastoma; Homeostasis; Humans; Liver Neoplasms; Phosphorylcholine
PubMed: 25934232
DOI: 10.1016/j.bcp.2015.04.015 -
Pharmaceutical Research May 2020Hemolysis is a serious side effect of antitumor alkylphospholipids (APLs) that limits dose levels and is a constraint in their use in therapeutic regimen. Nine prodrugs...
PURPOSE
Hemolysis is a serious side effect of antitumor alkylphospholipids (APLs) that limits dose levels and is a constraint in their use in therapeutic regimen. Nine prodrugs of promising APLs (miltefosine, perifosine, and erufosine) were synthesized so as to decrease their membrane activity and improve their toxicity profile while preserving their antineoplastic potency.
METHODS
The synthesis of the pro-APLs was straightforwardly achieved in one step starting from the parent APLs. The critical aggregation concentration of the prodrugs, their hydrolytic stability under various pH conditions, their blood compatibility and cytotoxicity in three different cell lines were determined and compared to those of the parent antitumor lipids.
RESULTS
The APL prodrugs display antitumor activity which is similar to that of the parent alkylphospholipids but without associated hemolytic toxicity.
CONCLUSION
The pro-APL compounds may be considered as intravenously injectable derivatives of APLs. They could thus address one of the major issues met in cancer therapies involving antitumor lipids and restricting their utilization to oral and topical administration because of limited maximum tolerated dose.
Topics: Administration, Intravenous; Antineoplastic Agents; Cell Line, Tumor; Drug Screening Assays, Antitumor; Drug Stability; Hemolysis; Humans; Maximum Tolerated Dose; Neoplasms; Organophosphates; Phosphorylcholine; Prodrugs; Quaternary Ammonium Compounds
PubMed: 32462253
DOI: 10.1007/s11095-020-02830-y -
Particle and Fibre Toxicology Jan 2024As the demand and application of engineered nanomaterials have increased, their potential toxicity to the central nervous system has drawn increasing attention....
BACKGROUND
As the demand and application of engineered nanomaterials have increased, their potential toxicity to the central nervous system has drawn increasing attention. Tunneling nanotubes (TNTs) are novel cell-cell communication that plays a crucial role in pathology and physiology. However, the relationship between TNTs and nanomaterials neurotoxicity remains unclear. Here, three types of commonly used engineered nanomaterials, namely cobalt nanoparticles (CoNPs), titanium dioxide nanoparticles (TiONPs), and multi-walled carbon nanotubes (MWCNTs), were selected to address this limitation.
RESULTS
After the complete characterization of the nanomaterials, the induction of TNTs formation with all of the nanomaterials was observed using high-content screening system and confocal microscopy in both primary astrocytes and U251 cells. It was further revealed that TNT formation protected against nanomaterial-induced neurotoxicity due to cell apoptosis and disrupted ATP production. We then determined the mechanism underlying the protective role of TNTs. Since oxidative stress is a common mechanism in nanotoxicity, we first observed a significant increase in total and mitochondrial reactive oxygen species (namely ROS, mtROS), causing mitochondrial damage. Moreover, pretreatment of U251 cells with either the ROS scavenger N-acetylcysteine or the mtROS scavenger mitoquinone attenuated nanomaterial-induced neurotoxicity and TNTs generation, suggesting a central role of ROS in nanomaterials-induced TNTs formation. Furthermore, a vigorous downstream pathway of ROS, the PI3K/AKT/mTOR pathway, was found to be actively involved in nanomaterials-promoted TNTs development, which was abolished by LY294002, Perifosine and Rapamycin, inhibitors of PI3K, AKT, and mTOR, respectively. Finally, western blot analysis demonstrated that ROS and mtROS scavengers suppressed the PI3K/AKT/mTOR pathway, which abrogated TNTs formation.
CONCLUSION
Despite their biophysical properties, various types of nanomaterials promote TNTs formation and mitochondrial transfer, preventing cell apoptosis and disrupting ATP production induced by nanomaterials. ROS/mtROS and the activation of the downstream PI3K/AKT/mTOR pathway are common mechanisms to regulate TNTs formation and mitochondrial transfer. Our study reveals that engineered nanomaterials share the same molecular mechanism of TNTs formation and intercellular mitochondrial transfer, and the proposed adverse outcome pathway contributes to a better understanding of the intercellular protection mechanism against nanomaterials-induced neurotoxicity.
Topics: Proto-Oncogene Proteins c-akt; Reactive Oxygen Species; Phosphatidylinositol 3-Kinases; Nanotubes, Carbon; TOR Serine-Threonine Kinases; Neuroglia; Adenosine Triphosphate; Apoptosis; Cell Membrane Structures; Nanotubes
PubMed: 38225661
DOI: 10.1186/s12989-024-00562-0 -
European Journal of Pharmacology May 2021Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) mutation in colon cancer contributes to the poor prognosis of the disease and...
Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) mutation in colon cancer contributes to the poor prognosis of the disease and chemoresistance of tumors. New therapies are needed; however, the lack of knowledge of the mechanism of chemoresistance has hindered progress. In this study, we investigated the mechanism of the reduced sensitivity of colon cancer cells to 5-fluorouracil (5-FU) and oxaliplatin (L-OHP), and the effects of perifosine, an Akt inhibitor that enhances the cytotoxicity of 5-FU and L-OHP in colon cancer cells harboring the PIK3CA mutation. The use of 5-FU or L-OHP alone or in combination induced significant death of Caco-2 cells (PIK3CA wild type), but only weakly decreased the viability of DLD-1 and SW948 cells harboring the PIK3CA mutation. The use of 5-FU and L-OHP, either alone or in combination, strongly suppressed Akt activation, Survivin, Bcl-2, and Bcl-xL expression, and enhanced Puma, phospho-p53, and p53 expression in Caco-2 cells than in DLD-1 cells. In addition, perifosine enhanced the cytotoxicity of the 5-FU and L-OHP combination, inhibited Akt activation and the expression of Survivin, Bcl-2, and Bcl-xL, and increased the expression of Puma, phospho-p53, and p53 in DLD-1 cells. These results indicate that PIK3CA mutation contributes to reduced sensitivity to 5-FU and L-OHP via Akt activation in colon cancer cells. Perifosine increases the efficacy of 5-FU and L-OHP by suppressing Akt activation. Thus, the use of an Akt inhibitor in combination with 5-FU and L-OHP may be beneficial in colon cancer with cells harboring the PIK3CA mutation.
Topics: Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Apoptosis Regulatory Proteins; Caco-2 Cells; Class I Phosphatidylinositol 3-Kinases; Colonic Neoplasms; Drug Resistance, Neoplasm; Fluorouracil; Gene Expression Regulation, Neoplastic; Humans; Mutation; Oxaliplatin; Phosphorylation; Phosphorylcholine; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-akt; Signal Transduction
PubMed: 33662352
DOI: 10.1016/j.ejphar.2021.173957