Cytochrome P450 (CYP) 4Z1, a novel CYP4 family member, is over-expressed in human mammary carcinoma and associated with high-grade tumors and poor prognosis. However, the precise role of CYP4Z1 in tumor progression is unknown. Here, we demonstrate that CYP4Z1 overexpression promotes tumor angiogenesis and growth in breast cancer. Stable expression of CYP4Z1 in T47D and BT-474 human breast cancer cells significantly increased mRNA expression and production of vascular endothelial growth factor (VEGF)-A, and decreased mRNA levels and secretion of tissue inhibitor of metalloproteinase-2 (TIMP-2), without affecting cell proliferation and anchorage-independent cell growth in vitro. Notably, the conditioned medium from CYP4Z1-expressing cells enhanced proliferation, migration and tube formation of human umbilical vein endothelial cells, and promoted angiogenesis in the zebrafish embryo and chorioallantoic membrane of the chick embryo. In addition, there were lower levels of myristic acid and lauric acid, and higher contents of 20-hydroxyeicosatetraenoic acid (20-HETE) in CYP4Z1-expressing T47D cells compared with vector control. CYP4Z1 overexpression significantly increased tumor weight and microvessel density by 2.6-fold and 1.9-fold in human tumor xenograft models, respectively. Moreover, CYP4Z1 transfection increased the phosphorylation of ERK1/2 and PI3K/Akt, while PI3K or ERK inhibitors and siRNA silencing reversed CYP4Z1-mediated changes in VEGF-A and TIMP-2 expression. Conversely, HET0016, an inhibitor of the CYP4 family, potently inhibited the tumor-induced angiogenesis with associated changes in the intracellular levels of myristic acid, lauric acid and 20-HETE. Collectively, these data suggest that increased CYP4Z1 expression promotes tumor angiogenesis and growth in breast cancer partly via PI3K/Akt and ERK1/2 activation.
The precise delivery and controllable release of carbon monoxide (CO) to tumor tissues is an emerging anticancer therapy because CO in a high dose can be detrimental to cell survival and tumor growth. However, CO gas therapy is limited by the gaseous nature of CO that hinders its enrichment and controllable release to tumor tissues. Here, a novel photodynamic therapy (PDT)-driven CO controllable release system (CORM@G3DSP-Ce6) that integrates the photosensitizer chlorin e6 (Ce6) and H 2 O 2 -sensitive CO releasing molecule CORM-401 into peptide dendrimer-based nanogels (G3DSP) is described. Upon excitation with near-infrared light, Ce6-mediated photochemical effect not only promotes the efficient cellular internalization of CORM@G3DSP-Ce6, but also triggers the rapid intracellular CO release from CORM-401 by depleting the H 2 O 2 produced during PDT. Importantly, the PDT-driven CO release does not impair the generation capability of singlet oxygen ( 1 O 2 ). As a result, accompanied with the simultaneous generation of large amounts of 1 O 2 and CO in cells, the combination of PDT and CO gas therapy offers significant synergistic anticancer effects and superior therapeutic safety both in vitro and in vivo.CORM-401 is a novel water-soluble CORM with multifaceted therapeutic potential. [11] First, the amount of CO released from CORM-401 is much higher than other CORMs. It is three times higher than commercially available CORM-3. CORM-401 is relatively stable. It is stable in phosphate buffered saline (PBS, pH 7.4) for several hours and thus will not likely release CO prematurely during circulation. CORM-401 releases CO via oxidation. The release rate is significantly increased in the presence of biologically relevant oxidants, such as hydrogen peroxide (H 2 O 2 ), [11,12] suggesting that CORM-401 is capable of intracellular release of CO, as long as CORM-401 can be efficiently delivered to the cells with significantly elevated H 2 O 2 levels.Photodynamic therapy (PDT) is a clinically approved and minimally invasive cancer treatment. The therapeutic effect of PDT is attributed to the large amounts of reactive oxygen species (ROS) produced by photosensitizer (PS) under NIR light. This induces rapid apoptosis of cancer cells. [13] The ROS generated by PS under a short period of low energy density irradiation can increase the cell membrane permeability and enhance the cellular uptake of nanoparticles-this is known "photochemical internalization" (PCI). [14] In addition, the PDT process is always accompanied by intracellular production of H 2 O 2 -one of the most stable agent of ROS. These unique merits make PDT an ideal candidate to promote the cellular uptake of CORM-401 and drive intracellular CO release. Moreover, PDT itself is also an anticancer treatment strategy. When used in tandem, these tools could significantly improve the anticancer effects.However, it remains unclear whether taking advantage of PDT effect for driving intracellular CO release would weaken the anticancer effects of PDT. Singlet oxygen ( 1 O 2...
The development of alternative strategies for the efficient treatment of subcutaneous abscesses that do not require the massive use of antibiotics and surgical intervention is urgently needed. Herein, a novel synergistic antibacterial strategy based on photodynamic (PDT) and NO gas therapy is reported, in which, a PDT‐driven NO controllable generation system (Ce6@Arg‐ADP) is developed with l‐Arg‐rich amphiphilic dendritic peptide (Arg‐ADP) as a carrier. This carrier not only displays superior bacterial association and biofilm penetration performance, but also acts as a versatile NO donor. Following efficient penetration into the interior of the biofilms, Ce6@Arg‐ADP can rapidly produce massive NO via utilizing the H2O2 generated during PDT to oxidize Arg‐ADP to NO and l‐citrulline, without affecting singlet oxygen (1O2) production. The combination of 1O2 and the reactive by‐products of NO offers notable synergistic antibacterial and biofilm eradication effects. Importantly, following efficient elimination of all bacteria from the abscess site, Arg‐ADP can further generate trace quantities of NO to facilitate the angiogenesis and epithelialization of the wound tissues, thereby notably promotes wound healing. Together, this study clearly suggests that Arg‐ADP is a versatile NO donor, and the combination of PDT and NO represents a promising strategy for the efficient treatment of subcutaneous abscesses.
Sonodynamic therapy (SDT), which is based on photodynamic therapy (PDT), is a new cancer treatment modality. Unlike PDT, which has poor tissue penetration, ultrasound can penetrate deeply into tissues and largely target tumor tissue to mediate the cytotoxicity of sonosensitizers. We hypothesize that, similar to PDT, SDT may perform effectively as a cancer vaccine. Thus, we developed a therapeutic strategy to explore whether SDT can eliminate primary tumors, inhibit metastases, and prevent tumor relapse. In the present study, we found that HiPorfin (HPD)‐induced SDT killed tumor cells, promoted calreticulin expression on the cell surface and elicited immune responses. Meanwhile, we observed that SDT induced functional antitumor vaccination and abscopal effects in H22 tumor‐bearing mice. Furthermore, this strategy conferred an immunological memory, which could protect against tumor recurrence after the elimination of the initial tumor. These results showed important effects of SDT on immune responses.
Polymeric vectors have shown great promise in the development of safe and efficient gene delivery systems; however, only a few have been developed in clinical settings due to poor transport across multiple physiological barriers. To address this issue and promote clinical translocation of polymeric vectors, a new type of polymeric vector, bioreducible fluorinated peptide dendrimers (BFPDs), was designed and synthesized by reversible cross-linking of fluorinated low generation peptide dendrimers. Through masterly integration all of the features of reversible cross-linking, fluorination, and polyhedral oligomeric silsesquioxane (POSS) core-based peptide dendrimers, this novel vector exhibited lots of unique features, including (i) inactive surface to resist protein interactions; (ii) virus-mimicking surface topography to augment cellular uptake; (iii) fluorination-mediated efficient cellular uptake, endosome escape, cytoplasm trafficking, and nuclear entry, and (iv) disulfide-cleavage-mediated polyplex disassembly and DNA release that allows efficient DNA transcription. Noteworthy, all of these features are functionally important and can synergistically facilitate DNA transport from solution to the nucleus. As a consequences, BFPDs showed excellent gene transfection efficiency in several cell lines (∼95% in HEK293 cells) and superior biocompatibility compared with polyethylenimine (PEI). Meanwhile BFPDs provided excellent serum resistance in gene delivery. More importantly, BFPDs offer considerable in vivo gene transfection efficiency (in muscular tissues and in HepG2 tumor xenografts), which was approximately 77-fold higher than that of PEI in luciferase activity. These results suggest bioreducible fluorinated peptide dendrimers are a new class of highly efficient and safe gene delivery vectors and should be used in clinical settings.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.