Human papillomavirus (HPV)-induced cervical cancer is a major health issue among women from the poorly/under-developed sectors of the world. It accounts for a high-mortality rate because of its late ...diagnosis and poor prognosis. Initial establishment and subsequent progression of this form of cancer are completely dependent on two major oncogenes E6 and E7, which are expressed constitutively leading to tumorigenesis. Thus, manipulation of these genes represents the most successful form of cervical cancer therapy. In the present article, information on structural, functional, and clinical dimensions of E6 and E7 activity has been reviewed. The genome organization and protein structure of E6 and E7 have been discussed followed by their mechanism to establish the six major cancer hallmarks in cervical tissues for tumor propagation. The later section of this review article deals with the different modes of therapeutics, which functions by deregulating E6 and E7 activity. Since E6 and E7 are the biomarkers of a cervical cancer cell and are the ones driving the cancer progression, therapeutic approaches targeting E6 and E7 have been proved to be highly efficient in terms of focused removal of abnormally propagating malignant cells. Therapeutics including different forms of vaccines to advanced genome editing techniques, which suppress E6 and E7 activity, have been found to successfully bring down the population of cervical cancer cells infected with HPV. T-cell mediated immunotherapy is another upcoming successful form of treatment to eradicate HPV-infected tumorigenic cells. Additionally, therapeutics using natural compounds from plants or other natural repositories, i.e., phytotherapeutic approaches have also been reviewed here, which prove their anticancer potential through E6 and E7 inhibitory effects. Thus, E6 and E7 repression through any of these methods is a significant approach toward cervical cancer therapy, described in details in this review along with an insight into the signaling pathways and molecular mechanistic of E6 and E7 action.
•PPy@MnO2-BSA(Ce6) NPs possess favorable biocompatibility and colloidal stability.•It could produce the cellular toxic reactive oxygen species to kill tumor.•PPy-PVP NPs exhibit high photothermal ...conversion ability.•PPy@MnO2-BSA(Ce6) NPs could relieve the hypoxia by catalyze H2O2 into oxygen.•PPy@MnO2-BSA(Ce6) NPs were used for imaging guided photo-therapy of tumor.
In this research, a novel nanoenzyme-based theranostic nanoplatform, named PPy@MnO2-BSA (bovine serum albumin (BSA)-modified manganese dioxide (MnO2)/polypyrrole (PPy)) was invented for T1-MRI-guided combined photothermal therapy (PTT) and photodynamic therapy (PDT) of tumors. The materials design was based on the in-situ oxidation and polymerization of pyrrole, using potassium permanganate (KMnO4) as the oxidant. The formed PPy@MnO2-BSA was further used to load with Ce6, via physical absorption. The PPy, with a high absorbance within the near-infrared (NIR) region, endowes the nanoenzyme with outstanding photothermal performance with the photo-to-heat conversion efficiency of 21.05%, while the MnO2, which could reduce the relaxation time of nearby protons, serves to enhance the tumor T1-MRI ability. Moreover, upon exposure to red light, the PPy@MnO2-BSA(Ce6) nanoparticle could produce the cellular toxic reactive oxygen species (ROS, i.e., 1O2) to trigger the tumor PDT. Meanwhile, the nanoparticle could continuously catalyze H2O2 into endogenous oxygen, to not only relieve the hypoxia inside the tumor but also enhance the tumor PDT effect. The in vitro and in vivo experiments both affirmed the great potential of PPy@MnO2-BSA(Ce6) nanoparticle in MRI-guided combined PDT and PTT for tumor. This research lays a solid foundation for the theoretical design and clinical application of theranostic nanoprobe in the future.
Chemodynamic therapy (CDT) employs Fenton catalysts to kill cancer cells by converting intracellular hydrogen peroxide (H2O2) into hydroxyl radicals (OH•). Although many studies on H2O2 ...supplementation have been conducted to improve the therapeutic effect of CDT, few studies have focused on the application of superoxide radical (O2−•) in CDT, which may result in better efficacy. A major concern about O2−•‐mediated CDT is its tendency to induce serious oxidative damage to normal tissues, which may be addressed by using a degradable O2−• scavenger. Here, a harmless‐harmful switchable and uninterrupted laccase (LAC)‐instructed killer (HULK) is constructed, which is the first CDT agent accelerated by LAC‐instructed O2−• generation and possesses a harmless‐harmful switchable effect because of the photodegradation of the O2−• scavenger iron‐chlorin e6 (FeCe6). LAC‐instructed substrate oxidation effectively catalyzes O2−• production with the help of intracellular reduction, thereby promoting the conversion of Fe3+ to Fe2+, accelerating the generation of OH•, and inducing tumor cell apoptosis and necrosis. The introduced O2−• scavenger FeCe6 is quickly photodegraded during irradiation, while LAC‐instructed O2−• generation proceeds as before, resulting in activatable CDT. This work not only provides the first strategy for LAC‐instructed O2−• generation but also presents new insight into activatable CDT.
A harmless–harmful switchable and uninterrupted laccase (LAC)‐instructed killer (HULK) is designed as a chemodynamic therapy (CDT) agent, which is the first CDT agent accelerated by LAC‐instructed superoxide radical (O2−•) generation and possesses harmless–harmful switchable effect because of the photodegradation of O2−• scavenger Fe‐chlorin e6, showing great potential as a safe and effective CDT agent.
The generation of reactive oxygen species (ROS) at the tumor site to induce destruction is emerging as a novel strategy for cancer treatment, which involves photodynamic therapy (PDT). Nevertheless, ...tumors typically create a hypoxic environment and are equipped with an endogenous antioxidant defense system that could potentially impede the efficiency of the therapeutic approach. To overcome these drawbacks, herein, a tumor microenvironment-responsive the ND-PAA-CD-Ce6@MnO2 (NPCC@M) delivery system was fabricated by disulfide bond coupling chlorin e6 (Ce6) to nanodiamond (ND) and further wrapped by MnO2 nanosheets to facilitate PDT. The use of disulfide bond not only stabilizes Ce6 in the blood circulation to prevent premature leakage, but also destroys the antioxidant barrier of overexpressed glutathione (GSH) in tumor cells. Moreover, the outer MnO2 was rapidly degraded by the endogenous hydrogen peroxide (H2O2) in the acidic pH and GSH within the tumor cells, which leads to an abundance of O2 and while increases the level of 1O2 under laser irradiation. The results eventually broke the redox homeostasis and attenuate hypoxia, thereby inducing apoptosis and necrosis of tumor cells. Detailed in vitro and in vivo biological effect has revealed a good biosafety profile and a high tumor suppression effect. Such a novel ND-based system with tumor microenvironment-modulating capability to elevate oxygen content and promote GSH consumption in tumor cells opens new opportunities for enhanced ROS treatment paradigms.
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•The NPCC@M nanoparticles confer Chlorin e6 targeting selectivity and enhanced photodynamic therapy.•External MnO2 of NPCC@M catalyzes the endogenous H2O2 inside tumors to produce O2, alleviating tumor hypoxia.•GSH consumption through the MnO2 and the destruction of disulfide bonds breaks redox homeostasis inside tumors.
Cancer photodynamic therapy (PDT) represents an attractive local treatment in combination with immunotherapy. Successful cancer PDT relies on image guidance to ensure the treatment accuracy. However, ...existing nanotechnology for co-delivery of photosensitizers and image contrast agents slows the clearance of PDT agents from the body and causes a disparity between the release profiles of the imaging and PDT agents. We have found that the photosensitizer Chlorin e6 (Ce6) is inherently bound to immunoglobulin G (IgG) in a nanomolarity range of affinity. Ce6 and IgG self-assemble to form the nanocomplexes termed Chloringlobulin (Chlorin e6 + immunoglobulin G). Chloringlobulin enhances the Ce6 concentration in the tumor without changing its elimination half-life in blood. Utilizing the immune checkpoint inhibitor antiprogrammed death ligand 1 (PD-L1) (αPD-L1) to prepare αPD-L1 Chloringlobulin, we have demonstrated a combination of Ce6-based red-light fluorescence image-guided surgery, stereotactic PDT, and PD-L1 blockade therapy of mice bearing orthotopic glioma. In mice bearing an orthotopic colon cancer model, we have prepared another Chloringlobulin that allows intraoperative fluorescence image-guided PDT in combination with PD-L1 and cytotoxic T lymphocyte antigen 4 (CTLA-4) dual checkpoint blockade therapy. The Chloringlobulin technology shows great potential for clinical translation of combinatorial intraoperative fluorescence image-guided PDT and checkpoint blockade therapy.
This study aimed to improve the biological effectiveness and pharmacokinetic properties of chlorin e6, a second-generation photosensitizer (PS), for tumor photodynamic therapy (PDT). Herein, the ...novel 31-hexyloxy chlorin e6-based 152- or 131-amino acid derivatives 3a, 3b, 3c and 8 were synthesized and their photophysical properties and in vitro bioactivities such as phototoxicity against A549, HeLa and melanoma B16–F10 cells, reactive oxygen species (ROS) production and subcellular localization were evaluated. In addition, preferred target compounds were also investigated for their in vivo pharmacokinetic in SD rats and in vivo antitumor efficacies in C57BL/6 mice bearing melanoma B16–F10 cells. Apparently, simultaneous introduction of amino acid residue and n-hexyloxy chain in chlorin e6 made a significant improvement in photophysical properties, ROS production, in vitro and in vivo PDT efficacy. Encouragingly, all target compounds showed higher in vitro phototoxicity than Talaporfin, and that 3c (152-Lys) exhibited strongest phototoxicity and highest dark toxicity/phototoxicity ratio, followed by 8 (131-Asp), 3a (152-Asp) and 3b (152-Glu). Moreover, in vivo PDT antitumor efficacy of 3a, 3c and 8 was all better than that of Talaporfin, and that both 3c and 8 had stronger PDT antitumor efficiency than 3a. The overall results suggested that these novel 31-hexyloxy chlorin e6-based 152- or 131-amino acid derivatives, especially 3c and 8, might be potential antitumor candidate drugs for clinical treatment of melanoma by PDT.
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•The 31-hexyloxy chlorin e6-based 152- or 131-amino acid derivatives were synthesized.•In vitro photodynamic activity and mechanism of target compounds were investigated.•In vivo antitumor potency and pharmacokinetic of target compounds were evaluated.•In vitro and in vivo PDT antitumor efficacy of 3a, 3c, 8 were better than Talaporfin.•In vitro and in vivo PDT antitumor efficacy of 3c and 8 were superior to 3a.
Purpose
This study aims to explore the expression of hnRNP K in cervical carcinogenesis and to investigate the regulatory role of hnRNP K on HPV16 oncogene expression as well as biological changes in ...cervical cancer cells.
Methods
In total 1042 subjects, including 573 with the normal cervix and 469 with different grades of cervical lesions were enrolled in this study to explore the association between hnRNP K and HPV16 oncogene expression in cervical carcinogenesis. Additionally, the Gene Omnibus (GEO) database was used to analyze hnRNP K mRNA expression in cervical cancerization. Meanwhile, the effects of hnRNP K on cell biological functions and HPV16 oncogene expression were investigated in Siha cells. Moreover, Function analyses were conducted using Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) databases after ChIP-seq.
Results
hnRNP K was highly expressed in cervical cancer and precancerous lesions, and positively correlated with HPV16 E6, but negatively correlated with HPV16 E2 and HPV16 E2/E6 ratio. hnRNP K induced cell proliferation, inhibited apoptosis and caused cell cycle arrest in the S phase, and particularly increased HPV16 E6 protein expression.
Conclusion
This study revealed that hnRNP K overexpression has important warning significance for the malignant transformation of cervical lesions, and could be used as a potential therapeutic target for inhibiting the carcinogenicity of HPV16 and prevention of cervical carcinogenesis.
•HPV-16 E6/E7 oncogenes are altenatively spliced in 3 products, E6*I, E6*II & E6^E7.•The role of HPV-16 E6 to produce apoptosis resistance in infected cells, is known.•The role of the E6 short forms ...on apoptosis resistance is unclear.•C·33-A cells transfected with the E6 short forms shown differential apoptosis.•E6*I and E6*II displayed opposite effects on cisplatin-induced apoptosis.
The HPV-16 E6/E7 bicistronic immature transcript produces 4 mature RNAs: the unspliced HPV-16 E6/E7pre−mRNA product and 3 alternatively spliced mRNAs. The 3 spliced mRNAs encode short forms of the E6 oncoprotein, namely E6*I, E6*II and E6^E7. In this study we showed that transfection of C-33A cells with monocistronic constructs of these cDNAs fused to GFP, produced different effects on apoptosis, after the treatment with cisplatin. Transfection of C-33A cells with the full-length E6-GFP oncoprotein resulted in a 50% decrease in cell death, while the transfection with the E6*I-GFP construct showed only a 25% of diminution of cell death, compared to the control cells. Transfection with the E6^E7-GFP or E7-GFP construct had no effect on the number of the apoptotic cells, compared with control cells. Conversely, transfection with the E6*II construct resulted in higher cell death than the control cells. Taken together, these results suggested that E6*I or E6*II, the short forms of HPV-16 E6, displayed opposite effects on cisplatin-induced apoptosis, when transfected in C-33A cells.
A variety of therapies have been developed and used for the treatment of colon cancer, however, the high mortality rate remains high and more effective strategies are still in urgent needs. In this ...study, an immunotherapy approach that is composed of innate immune activator Astragaloside III (As) and the photodynamic therapy (PDT) reagent chlorine e6 (Ce6) ((As + Ce6)@MSNs-PEG), was developed for colon cancer treatment. We showed that (As + Ce6)@MSNs-PEG could effectively activate NK cells and inhibit the proliferation of tumor cells in vitro. It could also effectively reach tumor sites, induce infiltration of immune cells into the tumor, and enhance the cytotoxicity of natural killer cells and CD8+ T cells in vivo. Without obvious side effects, (As + Ce6)@MSNs-PEG treatment significantly inhibited tumor growth and extended the lifespan of tumor-bearing mice. Further results revealed that treatment of (As + Ce6)@MSNs-PEG led to enhanced IFN secretion by immune cells and increased T-box transcription factor (T-bet), which is highly expressed by T cells. Therefore, (As + Ce6)@MSNs-PEG may serve as an effective and safe platform for combinatory use with nano-herb medicine and PDT to provide a new therapy for colon cancer treatment.
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