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Cancer is a worldwide problem afflicting 19 million people. Inhibition of DNA synthesis has been a cornerstone of anticancer therapy. A variety of chemotherapy drugs have been developed and many of these are aimed at inhibiting DNA synthesis, as they damage DNA, form DNA adduct and interfere with DNA synthesis. Another type of chemotherapy interferes with the synthesis of nucleotide pools. There are also other types of drugs that inhibit topoisomerases resulting in the interference with DNA replication and transcription. Significant progress has been made regarding radiation therapy that includes X-ray (and γ-ray), proton therapy and heavy ion therapy. The Auger therapy is a type of radiation therapy that differs from X-ray, proton or heavy ion therapy. The method relies on the use of high Z elements such as gadolinium, iodine, gold or silver. Irradiation of these elements results in the release of electrons including the Auger electrons that have strong DNA damaging effect. Tamanoi et al. developed novel nanoparticles containing gadolinium or iodine to place high Z elements at the periphery of the nucleus thus localizing them close to DNA. Irradiation with monochromatic X-ray resulted in the formation of double-strand DNA breaks leading to the destruction of tumor mass. Comparison of conventional X-ray therapy and the Auger therapy is discussed., (Copyright © 2022 Elsevier Inc. All rights reserved.)

X-ray irradiation of high Z elements causes photoelectric effects that include the release of Auger electrons that can induce localized DNA breaks. We have previously established a tumor spheroid-based assay that used gadolinium containing mesoporous silica nanoparticles and synchrotron-generated monochromatic X-rays. In this work, we focused on iodine and synthesized iodine-containing porous organosilica (IPO) nanoparticles. IPO were loaded onto tumor spheroids and the spheroids were irradiated with 33.2 keV monochromatic X-ray. After incubation in CO 2 incubator, destruction of tumor spheroids was observed which was accompanied by apoptosis induction, as determined by the TUNEL assay. By employing the γH2AX assay, we detected double strand DNA cleavages immediately after the irradiation. These results suggest that IPO first generate double strand DNA breaks upon X-ray irradiation followed by apoptosis induction of cancer cells. Use of three different monochromatic X-rays having energy levels of 33.0, 33.2 and 33.4 keV as well as X-rays with 0.1 keV energy intervals showed that the optimum effect of all three events (spheroid destruction, apoptosis induction and generation of double strand DNA breaks) occurred with a 33.2 keV monochromatic X-ray. These results uncover the preferential effect of K-edge energy X-ray for tumor spheroid destruction mediated by iodine containing nanoparticles., (© 2021. The Author(s).)

Biodegradable periodic mesoporous organosilica (BPMO) has recently emerged as a promising type of mesoporous silica-based nanoparticle for biomedical applications. Like mesoporous silica nanoparticles (MSN), BPMO possesses a large surface area where various compounds can be attached. In this work, we attached boronophenylalanine ( 10 BPA) to the surface and explored the potential of this nanomaterial for delivering boron-10 for use in boron neutron capture therapy (BNCT). This cancer therapy is based on the principle that the exposure of boron-10 to thermal neutron results in the release of a-particles that kill cancer cells. To attach 10 BPA, the surface of BPMO was modified with diol groups which facilitated the efficient binding of 10 BPA, yielding 10 BPA-loaded BPMO ( 10 BPA-BPMO). Surface modification with phosphonate was also carried out to increase the dispersibility of the nanoparticles. To investigate this nanomaterial's potential for BNCT, we first used human cancer cells and found that 10 BPA-BPMO nanoparticles were efficiently taken up into the cancer cells and were localized in perinuclear regions. We then used a chicken egg tumor model, a versatile and convenient tumor model used to characterize nanomaterials. After observing significant tumor accumulation, 10 BPA-BPMO injected chicken eggs were evaluated by irradiating with neutron beams. Dramatic inhibition of the tumor growth was observed. These results suggest the potential of 10 BPA-BPMO as a novel boron agent for BNCT.

Chick chorioallantoic membrane (CAM) assay provides a convenient and versatile model for the study of tumor formation, angiogenesis and metastasis. While the assay has been used for more than 100 years, the CAM assay has recently received renewed interest. One of the recent interests comes from the development of Precision Medicine in cancer therapy. The idea is to develop treatments that are tailor-made for each individual patient. For this to happen, patient-derived tumor models are critical and the CAM assay can make significant contribution. The other development concerns various applications of the CAM assay. Using this assay, various reagents have been identified. This includes sensitizers for radiation therapy and photodynamic therapy. We also discuss boron neutron capture therapy (BNCT) that is based on the splitting of boron-10 upon exposure to neutron beam. Recently, various boron-10 reagents have been developed and they can be examined for their efficacy for BNCT therapy using the CAM assay., (© 2019 Elsevier Inc. All rights reserved.)

Background: RHEB is a unique member of the RAS superfamily of small GTPases expressed in all tissues and conserved from yeast to humans. Early studies on RHEB indicated a possible RHEB-RAF interaction, but this has not been fully explored. Recent work on cancer genome databases has revealed a reoccurring mutation in RHEB at the Tyr35 position, and a recent study points to the oncogenic potential of this mutant that involves activation of RAF/MEK/ERK signaling. These developments prompted us to reassess the significance of RHEB effect on RAF, and to compare mutant and wild type RHEB., Methods: To study RHEB-RAF interaction, and the effect of the Y35N mutation on this interaction, we used transfection, immunoprecipitation, and Western blotting techniques. We generated cell lines stably expressing RHEB WT, RHEB Y35N, and KRAS G12V, and monitored cellular transforming properties through cell proliferation, anchorage independent growth, cell cycle analysis, and foci formation assays., Results: We observe a strong interaction between RHEB and BRAF, but not with CRAF. This interaction is dependent on an intact RHEB effector domain and RHEB-GTP loading status. RHEB overexpression decreases RAF activation of the RAF/MEK/ERK pathway and RHEB knockdown results in an increase in RAF/MEK/ERK activation. RHEB Y35N mutation has decreased interaction with BRAF, and RHEB Y35N cells exhibit greater BRAF/CRAF heterodimerization resulting in increased RAF/MEK/ERK signaling. This leads to cancer transformation of RHEB Y35N stably expressing cell lines, similar to KRAS G12 V expressing cell lines., Conclusions: RHEB interaction with BRAF is crucial for inhibiting RAF/MEK/ERK signaling. The RHEB Y35N mutant sustains RAF/MEK/ERK signaling due to a decreased interaction with BRAF, leading to increased BRAF/CRAF heterodimerization. RHEB Y35N expressing cells undergo cancer transformation due to decreased interaction between RHEB and BRAF resulting in overactive RAF/MEK/ERK signaling. Taken together with the previously established function of RHEB to activate mTORC1 signaling, it appears that RHEB performs a dual function; one is to suppress the RAF/MEK/ERK signaling and the other is to activate mTORC1 signaling.

Biodegradable PMO (Periodic Mesoporous Organosilica) has emerged as a promising type of mesoporous silica based nanoparticles for clinical translation. We as well as others have synthesized and characterized three types of nanoparticles containing disulfide, tetrasulfide or peptide-like bonds within their framework. Biodegradable PMO has high drug loading efficiency and can be taken up into cancer cells. Our experiments utilizing the chicken egg tumor model uncovered excellent capability to accumulate and deliver anticancer drugs to the tumor. These results will be described and their significance will be discussed. The chicken egg tumor model provides a convenient and versatile model for characterizing nanoparticles., (© 2018 Elsevier Inc. All rights reserved.)

Mesoporous silica nanoparticles (MSNs) provide a promising vehicle for anticancer drug delivery. Various animal studies point to the efficacy of this nanoparticle for delivering anticancer agents (drug and siRNA) to inhibit tumor growth. These studies also showed tumor accumulation of MSN nanoparticles. While the extent of tumor accumulation differed, the study showed that it is possible to achieve significant accumulation of nanoparticles in the tumor. Biocompatibility and safety of MSN were also demonstrated by these studies., (© 2018 Elsevier Inc. All rights reserved.)

Alterations of enzyme activity or enzyme levels in cancer tissue have been documented over the years. Taking advantage of these observations, various strategies for drug activation and drug delivery have been developed. One example is a mechanism called "prodrugs" that generates active drugs by enzyme cleavage. Another example is enzyme-induced anticancer drug release mechanisms. This system is constructed by incorporating enzyme-sensitive linkages to materials such as hydrogels and nanodelivery vehicles, including liposomes, polymer micelles, and mesoporous silica nanoparticles. Various release mechanisms for anticancer drugs and siRNA have been developed. In addition, enzyme cleavage is utilized in nanodelivery vehicles that contain nanomachines. One example is nanovalve that can be opened by enzyme cleavage. Another example is enzyme-induced release of nanoparticles from multistage vehicles. Finally, colon-specific drug delivery by azoreductase cleavable mechanism is discussed., (© 2017 Elsevier Inc. All rights reserved.)

Mevalonate (MVA) is synthesized from 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) by HMG-CoA reductase (HMG-CoAR). MVA is further metabolized to farnesyl pyrophosphate (FPP), a precursor of cholesterol and sterols. FPP is also converted to geranylgeranyl pyrophosphate, and these lipids are used for post-translational modification of proteins that are involved in various aspects of tumor development and progression. Many studies showed that the MVA pathway is up-regulated in several cancers such as leukemia, lymphoma, multiple myeloma; as well as breast, hepatic, pancreatic, esophageal and prostate cancers. Several mechanisms may be involved in dysregulation of this pathway. They include p53 mutation, a mutation in HMG-CoAR and sterol-regulatory element binding protein (SREBP) cleavage-activating protein SCAP as its regulator, PKB/Akt activation, decreased AMPK activation, and activation of transcription factors such as: SREBP and HIF-1. Statins as inhibitors of MVA pathway might be useful for cancer prevention and/or treatment through their interactions with essential cellular functions, such as cell proliferation and differentiation. Other inhibitors are also designed for inhibition of this key pathway and their mechanism of action was investigated. In the present review, we will first describe about some inhibitors of MVA, including statins that have been suggested for cancer treatment. We will then discuss about the mechanisms involved in MVA dysregulation, especially in cancer., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

Nanoparticles that respond to internal and external stimuli to carry out controlled release of anticancer drugs have been developed. In this review, we focus on the development of mesoporous silica based nanoparticles, as this type of materials provides a relatively stable material that is amenable to various chemical modifications. We first provide an overview of various designs employed to construct MSN-based controlled release systems. These systems respond to internal stimuli such as pH, redox state and the presence of biomolecules as well as to external stimuli such as light and magnetic field. They are at a different stage of development; depending on the system, their operation has been demonstrated in aqueous solution, in cancer cells or in animal models. Efforts to develop MSNs with multi-functionality will be discussed. Safety and biodegradation of MSNs, issues that need to be overcome for clinical development of MSNs, will be discussed. Advances in the synthesis of mechanized theranostic nanoparticles open up the possibility to start envisioning future needs for medical equipment., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Growth and progression of solid tumors depend on the integration of multiple pro-growth and survival signals, including the induction of angiogenesis. TWIST1 is a transcription factor whose reactivation in tumors leads to epithelial to mesenchymal transition (EMT), including increased cancer cell stemness, survival, and invasiveness. Additionally, TWIST1 drives angiogenesis via activation of IL-8 and CCL2, independent of VEGF signaling. In this work, results suggest that chemically modified siRNA against TWIST1 reverses EMT both in vitro and in vivo. siRNA delivery with a polyethyleneimine-coated mesoporous silica nanoparticle (MSN) led to reduction of TWIST1 target genes and migratory potential in vitro. In mice bearing xenograft tumors, weekly intravenous injections of the siRNA-nanoparticle complexes resulted in decreased tumor burden together with a loss of CCL2 suggesting a possible anti-angiogenic response. Therapeutic use of TWIST1 siRNA delivered via MSNs has the potential to inhibit tumor growth and progression in many solid tumor types., From the Clinical Editor: Tumor progression and metastasis eventually lead to patient mortality in the clinical setting. In other studies, it has been found that TWIST1, a transcription factor, if reactivated in tumors, would lead to downstream events including angiogenesis and result in poor prognosis in cancer patients. In this article, the authors were able to show that when siRNA against TWIST1 was delivered via mesoporous silica nanoparticle, there was tumor reduction in an in-vivo model. The results have opened up a new avenue for further research in this field., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Small molecule inhibitors against protein geranylgeranyltransferase-I such as P61A6 have been shown to inhibit proliferation of a variety of human cancer cells and exhibit antitumor activity in mouse models. Development of these inhibitors could be dramatically accelerated by conferring tumor targeting and controlled release capability. As a first step towards this goal, we have encapsulated P61A6 into a new type of liposomes that open and release cargos only under low pH condition. These low pH-release type liposomes were prepared by adjusting the ratio of two types of phospholipid derivatives. Loading of geranylgeranyltransferase-I inhibitor (GGTI) generated liposomes with average diameter of 50-100 nm. GGTI release in solution was sharply dependent on pH values, only showing release at pH lower than 6. Release of cargos in a pH-dependent manner inside the cell was demonstrated by the use of a proton pump inhibitor Bafilomycin A1 that Increased lysosomal pH and inhibited the release of a dye carried in the pH-liposome. Delivery of GGTI to human pancreatic cancer cells was demonstrated by the inhibition of protein geranylgeranylation inside the cell and this effect was blocked by Bafilomycin A1. In addition, GGTI delivered by pH-liposomes induced proliferation inhibition, G1 cell cycle arrest that is associated with the expression of cell cycle regulator p21CIP1/WAF1. Proliferation inhibition was also observed with various lung cancer cell lines. Availability of nanoformulated GGTI opens up the possibility to combine with other types of inhibitors. To demonstrate this point, we combined the liposomal-GGTI with farnesyltransferase inhibitor (FTI) to inhibit K-Ras signaling in pancreatic cancer cells. Our results show that the activated K-Ras signaling in these cells can be effectively inhibited and that synergistic effect of the two drugs is observed. Our results suggest a new direction in the use of GGTI for cancer therapy.

Mammalian target of rapamycin (mTOR) is a key regulator of eukaryotic cell growth. In particular, mTORC1, one of the two complexes that contain mTOR, is involved in the regulation of protein synthesis, proliferation, cell cycle and autophagy. Hyperactivation of the mTOR signaling pathway is observed in human cancer. A variety of approaches including deletion analysis, yeast genetic screens and mining of human cancer genome databases were taken that resulted in the identification of activating mutations of TOR. These studies suggest that the FAT, FRB and kinase domains are the three regions of TOR where activating mutations can be identified. Within the kinase domain, the mutations are clustered in three hot spots that are all located in the kinase active site that was deduced by the alignment with PI3K. One of the hot spots corresponds to the region where PI3K oncogenic mutations have been identified. These results are beginning to provide important insights into the mechanism of activation of mTOR., (© 2011 The Authors. Journal compilation © 2011 by the Molecular Biology Society of Japan/Blackwell Publishing Ltd.)

Mesoporous silica nanoparticles (MSNs) are a promising material for drug delivery. In this Full Paper, MSNs are first shown to be well tolerated, as demonstrated by serological, hematological, and histopathological examinations of blood samples and mouse tissues after MSN injection. Biodistribution studies using human cancer xenografts are carried out with in vivo imaging and fluorescent microscopy imaging, as well as with inductively coupled plasma mass spectroscopy. The results show that MSNs preferentially accumulate in tumors. Finally, the drug-delivery capability of MSNs is demonstrated by following tumor growth in mice treated with camptothecin-loaded MSNs. These results indicate that MSNs are biocompatible, preferentially accumulate in tumors, and effectively deliver drugs to the tumors and suppress tumor growth.

Protein methylation at the C-terminus of mammalian isoprenylated proteins has been implicated in membrane attachment, protein-protein interactions, and protein stability. A new paper describes surprising results: in the absence of methylation some target proteins have increased stability, whereas others have decreased stability. The decreased stability of the RhoA protein is correlated with an increased resistance to Ras-dependent transformation and suggests the basis for the development of a new approach to antitumor therapy.

Epithelial ovarian cancer (EOC) is the most deadly gynecologic malignancy on account of its late stage at diagnosis and frequency of drug resistant recurrences. Novel therapies to overcome these barriers are urgently needed. TWIST is a developmental transcription factor reactivated in cancers and linked to angiogenesis, metastasis, cancer stem cell phenotype, and drug resistance, making it a promising therapeutic target. In this work, we demonstrate the efficacy of TWIST siRNA (siTWIST) and two nanoparticle delivery platforms to reverse chemoresistance in EOC models. Polyamidoamine dendrimers and mesoporous silica nanoparticles (MSNs) carried siTWIST into target cells and led to sustained TWIST knockdown in vitro. Mice treated with cisplatin plus MSN-siTWIST exhibited lower tumor burden than mice treated with cisplatin alone, with most of the effect coming from reduction in disseminated tumors. This platform has potential application for overcoming the clinical challenges of metastasis and chemoresistance in EOC and other TWIST overexpressing cancers.

Nanoparticles that respond to internal and external stimuli to carry out controlled release of anticancer drugs have been developed. In this review, we focus on the development of mesoporous silica based nanoparticles, as this type of materials provides a relatively stable material that is amenable to various chemical modifications. We first provide an overview of various designs employed to construct MSN-based controlled release systems. These systems respond to internal stimuli such as pH, redox state and the presence of biomolecules as well as to external stimuli such as light and magnetic field. They are at a different stage of development; depending on the system, their operation has been demonstrated in aqueous solution, in cancer cells or in animal models. Efforts to develop MSNs with multi-functionality will be discussed. Safety and biodegradation of MSNs, issues that need to be overcome for clinical development of MSNs, will be discussed. Advances in the synthesis of mechanized theranostic nanoparticles open up the possibility to start envisioning future needs for medical equipment.

Growth and progression of solid tumors depend on the integration of multiple pro-growth and survival signals, including the induction of angiogenesis. TWIST1 is a transcription factor whose reactivation in tumors leads to epithelial to mesenchymal transition (EMT), including increased cancer cell stemness, survival, and invasiveness. Additionally, TWIST1 drives angiogenesis via activation of IL-8 and CCL2, independent of VEGF signaling. In this work, results suggest that chemically modified siRNA against TWIST1 reverses EMT both in vitro and in vivo. siRNA delivery with a polyethyleneimine-coated mesoporous silica nanoparticle (MSN) led to reduction of TWIST1 target genes and migratory potential in vitro. In mice bearing xenograft tumors, weekly intravenous injections of the siRNA-nanoparticle complexes resulted in decreased tumor burden together with a loss of CCL2 suggesting a possible anti-angiogenic response. Therapeutic use of TWIST1 siRNA delivered via MSNs has the potential to inhibit tumor growth and progression in many solid tumor types.From the clinical editorTumor progression and metastasis eventually lead to patient mortality in the clinical setting. In other studies, it has been found that TWIST1, a transcription factor, if reactivated in tumors, would lead to downstream events including angiogenesis and result in poor prognosis in cancer patients. In this article, the authors were able to show that when siRNA against TWIST1 was delivered via mesoporous silica nanoparticle, there was tumor reduction in an in-vivo model. The results have opened up a new avenue for further research in this field.