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HIV-PIs inhibit MMP gelatinolytic activity, reduce MMP-9 expression, and restore the basement membrane integrity in HPV16/E2 tumors. A and B, Confocal images of the in situ gelatin zymography (green) of representative cervical sections from mice treated with IDV/r or SQV/r (A), LPV/r (B), or controls (scale bars, 50 mm). Box plots show the percentage of gelatinolytic area over the total tissue area for IDV/r-, SQV/r-, or LPV/r-treated animals as compared with control mice. Gelatinolytic activity was greatly reduced in all treatment groups as compared with controls, as assessed by the nonparametric two-tailed, unpaired Mann-Whitney U test (n ¼ 5 mice/group). C and D, Real-time RT-PCR quantification of MMP-9 RNA expression in cervical tissues from HPV16/E2 mice. The copy number of MMP-9 RNA molecules from snap-frozen tissue samples of mice treated with IDV/r or SQV/r (C), or LPV/r (D) was normalized on control. A reduction of MMP-9 gene expression by 57%, 38%, and 58% was detected in mice treated with IDV/r, SQV/r, or LPV/r, respectively, as compared with control. Results were analyzed by Student t test (n ¼ 3 mice/ group). E and F, Confocal images of collagen IV expression at the basement membrane of cervical lesions and vessels in representative cervical cross-sections from mice treated with LPV/r or controls. Basement membrane integrity expression was quantified as the percentage of collagen IV-stained area over the total tissue area in the tumor lesions (E) or as percentage of colocalization of collagen IV with Meca32 in vessels (F). Results were analyzed by nonparametric two-tailed, unpaired Mann-Whitney U test (n ¼ 3 mice per group); scale bars, 50 mm.
Source publication
Antiretrovirals belonging to the HIV protease inhibitor (HIV-PI) class exert inhibitory effects across several cancer types by targeting tumor cells and its microenvironment. Cervical carcinoma (CC) represents a leading cause of morbidity and mortality, particularly in women doubly infected with high-risk human papillomaviruses (HR-HPV) and the hum...
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... mechanism by which HIV-PIs exert their antiangiogenic and pronormalizing effect in HPV16/E2 mice, MMP activity was evaluated in cervical lesions by an in situ gelatin zymography analysis (14). Treatment with IDV/r, SQV/r, or LPV/r significantly reduced MMP activity by 69%, 64%, and 72%, respectively, as compared with control buffer (P < 0.0001; Fig. 4A and B). Among the various MMPs, MMP-9 plays a prominent role in regulating cervical carcinoma progression and invasion in HPV16/E2 mice, as well as in human cervical carcinoma (15,17,25). Therefore, MMP-9 expression was evaluated in mice cervical lesions by real-time RT-PCR analysis. MMP-9 gene expression was significantly reduced in cervical ...
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... mice, as well as in human cervical carcinoma (15,17,25). Therefore, MMP-9 expression was evaluated in mice cervical lesions by real-time RT-PCR analysis. MMP-9 gene expression was significantly reduced in cervical carcinoma of mice treated with IDV/r, SQV/r, or LPV/r as compared with controls (P ¼ 0.0003, P ¼ 0.002, and P ¼ 0.0017, respectively; Fig. 4C and D). Results from immunofluorescence analysis performed in LPV/rtreated animals and their controls, indicate that this was associated with a 43% reduction of MMP-9 protein expression (P < 0.0001; Supplementary Fig. S2). Thus, treatment with HIV-PIs blocks both MMP-9 expression and activity in HPV16/E2 mice cervical carcinoma ...
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... HIV-PIs or control mice were assessed for collagen IV expression by immunostaining. Cervical carcinoma lesions of control mice were characterized by invading nests of cancer cells without evidence of encirclement by the basement membrane (25,28) or collagen IV expression (Supplementary Fig. S3). On the contrary, tumors of mice treated with LPV/r (Fig. 4E) appeared to be well-encapsulated and expressed significantly higher levels of collagen IV than controls (by 4.9-fold, P ¼ 0.0051), without evidence of micro-invasion (28). The same was observed in IDV/r-and SQV/rtreated mice (P < 0.0001; Supplementary Fig. S3). In addition, treatment with LPV/r significantly increased the amount of ...
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... observed in IDV/r-and SQV/rtreated mice (P < 0.0001; Supplementary Fig. S3). In addition, treatment with LPV/r significantly increased the amount of collagen IV by 2.7-fold in the basement membrane of tumor vasculature, as compared with control mice (P < 0.0001), therefore, indicating a restoration of the integrity of vascular basement membrane (Fig. 4F), one of the determinants of vascular normalization (35). Altogether, these HIV-PI treatment promotes tumor vasculature normalization and enhances antitumor effects of conventional chemotherapy in HPV16/E2 mice. A and B, Vascular pericyte coverage evaluated by immunostaining with Meca32 (green channel) and the pericyte marker, NG2 (red ...
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... with IDV/r, SQV/r, or LPV/r increased TIMP-3 expression by 2.5-, 2.1-, or 2.7-folds, respectively, as compared with control mice (P ¼ 0.0058, P ¼ 0.0036, P ¼ 0.0006, respectively; Fig. 5A). Interestingly, this effect occurred in the absence of a significant modulation of the expression of the other TIMPs ( Supplementary Fig. S4A-S4C). The effect of HIV-PI treatment on TIMP-3 expression was confirmed at the protein level by immunofluorescence analysis, showing extremely low levels of TIMP-3 protein expression within untreated tumors and a significant increase after IDV/r, SQV/r, and LPV/r treatment (P < 0.0001, for all treatment groups; Supplementary Fig. S5A and S5B). ...
Citations
... The lack of efficacy may be related to the non-molecularly targeted nature of our current anal dysplasia treatments for HPV-infected tissues. Given the previous literature demonstrating the targeted effects of protease inhibitors on HPV oncoproteins, we aimed to examine the role of topical protease inhibitors in a transgenic mouse model of anal disease [14][15][16][31][32][33][34]. ...
Anal cancer is a major health problem. This study seeks to determine if the topical protease inhibitor Saquinavir (SQV), is effective at the prevention of anal cancer in transgenic mice with established anal dysplasia. K14E6/E7 mice were entered into the study when the majority spontaneously developed high-grade anal dysplasia. To ensure carcinoma development, a subset of the mice was treated with a topical carcinogen: 7,12-Dimethylbenz[a]anthracene (DMBA). Treatment groups included: no treatment, DMBA only, and topical SQV with/without DMBA. After 20 weeks of treatment, anal tissue was harvested and evaluated histologically. SQV was quantified in the blood and anal tissue, and tissue samples underwent analysis for E6, E7, p53, and pRb. There was minimal systemic absorption of SQV in the sera despite high tissue concentrations. There were no differences in tumor-free survival between SQV-treated and respective control groups but there was a lower grade of histological disease in the mice treated with SQV compared to those untreated. Changes in E6 and E7 levels with SQV treatment suggest that SQV may function independently of E6 and E7. Topical SQV decreased histological disease progression in HPV transgenic mice with or without DMBA treatment without local side effects or significant systemic absorption.
... As a result, repurposing existing medications with proven tolerability, toxicity, and pharmacology is a potentially promising technique for cancer therapy development (Tuli et al., 2021;Zhang et al., 2020). Several investigations have found that antiretrovirals from the human immunodeficiency virus protease inhibitor (HIV-PI) class have anti-tumor effects across a variety of cancer types (Qiu et al., 2020). Growing body of evidence has reported and suggested the use of antiviral drugs as an adjuvant in cancer chemotherapy (Zhang et al., 2020;Shih et al., 2014). ...
HIV-protease inhibitor Ritonavir (RTV) is a clinical-stage drug. We exhibit here the synergistic effect of RTV coupled with cisplatin as potential combination therapy for treatment of cervical cancer. Knowledge about the interaction of RTV with the high-expression signatures in cancer is limited. Therefore, we utilized computational techniques to understand and assess the drug-binding affinity and drug-target interaction of RTV with these altered protein signatures. Computational studies revealed the potential interaction ability of RTV along with few other HIV protease inhibitors against these altered cancer targets. All targets exhibited good affinity towards RTV and the highest affinity was exhibited by CYP450 3A4, PDGFR and ALK. RTV established stable interaction with PDGFR and molecular dynamics simulation confirms their frequent interaction for 300 ns. Control docking of PDGFR with standard PDGFR inhibitor exhibited lower binding affinity when compared with RTV-PDGFR complex. In search of drugs as a part of combination therapy to reduce side effects of Cisplatin, this paper further evaluated the effect of combination of RTV and Cisplatin in cervical cancer cells. We propose several combination models that combines anti-viral drug RTV and standard chemotherapeutic agent, Cisplatin to be synergistic with CI value ranging from of 0.01 to 1.14. These observations suggest that anti-viral compound (RTV) could act synergistically with Cisplatin for cervical cancer therapy. However, further studies are warranted to investigate the combinatorial mode of action of RTV and Cisplatin on different molecular pathways to have a translational outcome in cervical cancer.
Communicated by Ramaswamy H. Sarma
... Anti-HIV drugs are also implicated in resolving deregulated cell cycle arrest and resistance to apoptosis during carcinogenesis (Maksimovic-Ivanic et al., 2017;Marima et al., 2020). The antitumour effect of anti-HIV drugs have been shown in a wide range of cancer types including skin cancer (Paskas et al., 2019), lymphoma (Kariya et al., 2014), glioblastoma (Gratton et al., 2018), thyroid cancer (Kushchayeva et al., 2014), Kaposi's sarcoma (Gantt et al., 2011) and cervical cancer (Qiu et al., 2020). ...
... HIV-PIs possess direct antitumour properties independent of their antiviral properties, and this was shown in several independent studies, which demonstrated that HIV-PIs exhibited antitumor and antiangiogenic effects independent of viral load and CD4 cell count Monini et al., 2003;Sgadari et al., 2003;Sgadari et al., 2011;Patton et al., 2013). The direct antitumour effects of HIV-PIs have been shown in cervical cancer (Barillari et al., 2012;Qiu et al., 2020), leukemia (Piccinini et al., 2005;Meier-Stephenson et al., 2017), lung cancer (Yang et al., 2006;Rengan et al., 2019), breast cancer (Srirangam et al., 2006;Soprano et al., 2016), glioblastoma (Pajonk et al., 2002;Rauschenbach et al., 2020), multiple myeloma (Ikezoe et al., 2004;Mendez-Lopez et al., 2019), melanoma (Jiang et al., 2007;Paskas et al., 2019), and ovarian cancer (Kumar et al., 2009;Perna et al., 2017). ...
... These effects remove the p53 and Rb-mediated G1 cell cycle checkpoint arrest (Lomazzi et al., 2002), thus promoting carcinogenesis. HIV protease inhibitors restore cell-cycle arrest and apoptosis, which are the most prominent outcomes of p53 activation (Qiu et al., 2020). In addition to their direct tumouricidal effects against cervical cancer cells, HIV-PIs have also been shown to curb the growth of lung cancer (Srirangam et al., 2011), breast cancer (Shim et al., 2012), colon cancer (Subeha and Telleria, 2020), and hepatic origin adenocarcinomas (Sun et al., 2012) by inhibiting the growth of new blood vessels that support the growth of tumours and their spread to other organs (Toschi et al., 2011). ...
Cervical cancer is a Human Papilloma virus-related disease, which is on the rise in a number of countries, globally. Two essential oncogenes, E6 and E7, drive cell transformation and cancer development. These two oncoproteins target two of the most important tumour suppressors, p53 and pRB, for degradation through the ubiquitin ligase pathway, thus, blocking apoptosis activation and deregulation of cell cycle. This pathway can be exploited for anticancer therapeutic interventions, and Human Immunodeficiency Virus Protease Inhibitors (HIV-PIs) have attracted a lot of attention for this anticancer drug development. HIV-PIs have proven effective in treating HPV-positive cervical cancers and shown to restore impaired or deregulated p53 in HPV-associated cervical cancers by inhibiting the 26S proteasome. This review will evaluate the role players, such as HPV oncoproteins involved cervical cancer development and how they are targeted in HIV protease inhibitors-induced p53 restoration in cervical cancer. This review also covers the therapeutic potential of HIV protease inhibitors and molecular mechanisms behind the HIV protease inhibitors-induced p53-dependent anticancer activities against cervical cancer.
... 15,16 Nevertheless, prolonged postoperative indwelling of the urethral catheter may affect the function of the urethral sphincter, weaken bladder tension and detrusor contraction, increase the pressure of the bladder and urethra during urination, and affect normal urination, thereby increasing the incidence of complications such as urinary retention and dysuria. 17 It is shown in this study that the incidence of catheter replacement, urinary retention, and dysuria in the observation group was significantly lower than that in the control group, indicating that Kegel pelvic floor muscle exercise based on clean intermittent self-catheterization can effectively reduce the risk of complications. Which is consistent with the results of previous studies. ...
Objectives:
To investigate the effect of Kegel pelvic floor muscle training combined with clean intermittent self-catheterization on patients with cervical cancer, and to analyze the risk factors affecting urinary retention.
Methods:
A total of 166 patients with cervical cancer admitted to our hospital from October 2016 to December 2019, all of whom received radical resection of cervical cancer, were divided into two groups according to the random number table method: the observation group and the control group, with 83 cases in each group. The control group underwent clean intermittent self-catheterization, while the observation group underwent Kegel pelvic floor muscle exercise combined with clean intermittent self-catheterization. The catheter replacement rate, bladder residual urine volume, self-perceived burden scale (SPB), Kolcaba general comfort questionnaire (GCQ), incidence of urinary tract infection, and urinary retention after catheter removal were compared between the two groups. Logistics regression analysis was utilized to analyze the risk factors affecting urinary retention.
Results:
The incidence of catheter replacement, urinary retention, dysuria and bladder residual urine volume in the observation group were significantly lower than those in the control group (P<0.05). Postoperative SPB score of the two groups decreased significantly, while the GCQ score increased significantly. Postoperative SPB score of the observation group was significantly lower than that of the control group, while the GCQ score was significantly higher than that of the control group (P<0.05). Statistically significant differences can be observed in the comparison of catheter indwelling time, urinary tract infection, surgical incision infection and surgical margin between the two groups (P<0.05). Logistic regression analysis showed that catheter indwelling time, urinary tract infection, surgical incision infection and surgical margin were independent risk factors affecting urinary retention (P<0.05).
Conclusions:
Catheter indwelling time, urinary tract infection, surgical incision infection and surgical margin are the risk factors for postoperative urinary retention in patients with cervical cancer. With Kegel pelvic floor muscle exercise combined with clean intermittent self-catheterization, a variety of benefits can be realized, such as improved bladder function, reduced incidence of urinary tract infections and urinary retention, as well as increased patient comfort.
Matrix metalloproteinase-9 (MMP-9), one of the most investigated and studied biomarkers of the MMPs family, is a zinc-dependent proteolytic metalloenzyme whose primary function is degrading the extracellular matrix (ECM). It has been proved that MMP-9 expression elevates in multiple pathological conditions, including thyroid carcinoma. MMP-9 has a detectable higher level in malignant or metastatic thyroid tumor tissues than in normal or benign tissues and acts as an additional marker to distinguish different tumor stages because of its close correlations with clinical features, such as lymph node metastasis, TNM stage, tumor size and so on. Natural and non-natural MMP-9 inhibitors suppress its expression, block the progression of diseases, and play a role in therapy consequently. MMP-9 inhibitory molecules also assist in treating thyroid tumors by suppressing the proliferation, invasion, migration, metastasis, viability, adhesion, motility, epithelial-mesenchymal transition (EMT), and other risk factors of different thyroid cancer cells. In a word, discovering and designing MMP-9 inhibitors provide great therapeutic effects and promising clinical values in various types of thyroid carcinoma.
Cancer is the main cause when the mutation in the genes occur which may be the lead to several type of mutations in our body. Usually cancer that is common by the mutation of genes is cervical cancer, breast cancer that may affect the body mechanism and directly effects on the targeting cells. By allowing one gene to produce numerous unique protein isoforms, alternative splicing contributes to the majority of protein diversity in higher eukaryotes. It adds an additional layer of control over gene expression. Alternative splicing is used to encode proteins with distinct functions in up to 95 percent of human multi-exon genes. Furthermore, alternative splicing is linked to about 15% of human genetic illnesses and malignancies. Mapping and quantifying alternative splicing events are important for downstream analysis, especially when disease is associated with them. Correct isoform expression from high-throughput RNA-seq data, on the other hand, remains a challenge. Alternative splicing is linked to a group of delicate machines that interact with one another to facilitate vital biological processes such as cell production and differentiation. We hope to demonstrate I) alternative splicing mechanisms and control, and II) alternative splicing-related human disease in this mini-review. III) computational approach used for measuring isoforms with alternative splicing which derived from RNA sequence.
