Nelfinavir is effective against human cervical cancer cells in vivo: a potential treatment modality in resource-limited settings

Davis, M.A.; Delaney, Joe R.; Patel, C. A.; Storgard, Ryan; Stupack, Dwayne G.

doi:10.2147/dddt.s102241

Cited by 7 publications

(4 citation statements)

References 43 publications

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“…The authors further observed an increase in apoptotic cells in tumors derived from TNBC xenografts identified by the positive terminal deoxynucleotidyl transferase (TdT) dUTP Nick-End Labelling (TUNEL) assay [ 41 ]. Davis and colleagues reported cleavage of caspase-7 in nelfinavir-treated cisplatin-sensitive and -resistant cervical cancer cells, which corroborated similar findings in breast cancer cells [ 42 , 43 ]. In pediatric leukemia cells treated with nelfinavir, PARP cleavage was associated with the cleavage of upstream apoptosis initiator caspase-9 [ 44 ].…”

Section: Potential Mechanisms Whereby Nelfinavir Exert Its Anti-casupporting

confidence: 55%

“…In a multidrug-resistant (MDR) breast cancer model (MCF-7/Dox), it was observed an increase in LC3II during combined treatment with nelfinavir and doxorubicin [ 60 ]. In nelfinavir-treated cisplatin-sensitive ME-180 and cisplatin-resistant (CPR) ME-180 cervical cancer cells, LC3II was also increased [ 42 ]. Increased LC3II expression was also seen in PBMCs of nelfinavir/lenalidomide/dexamethasone-treated lenalidomide-refractory MM patients [ 76 ].…”

Section: Potential Mechanisms Whereby Nelfinavir Exert Its Anti-camentioning

confidence: 99%

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The Anti-Cancer Properties of the HIV Protease Inhibitor Nelfinavir

Subeha

Telleria

2020

Cancers

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Traditional cancer treatments may lose efficacy following the emergence of novel mutations or the development of chemoradiotherapy resistance. Late diagnosis, high-cost of treatment, and the requirement of highly efficient infrastructure to dispense cancer therapies hinder the availability of adequate treatment in low-income and resource-limited settings. Repositioning approved drugs as cancer therapeutics may reduce the cost and timeline for novel drug development and expedite the availability of newer, efficacious options for patients in need. Nelfinavir is a human immunodeficiency virus (HIV) protease inhibitor that has been approved and is extensively used as an anti-infective agent to treat acquired immunodeficiency syndrome (AIDS). Yet nelfinavir has also shown anti-cancer effects in in vitro and in vivo studies. The anti-cancer mechanism of nelfinavir includes modulation of different cellular conditions, such as unfolded protein response, cell cycle, apoptosis, autophagy, the proteasome pathway, oxidative stress, the tumor microenvironment, and multidrug efflux pumps. Multiple clinical trials indicated tolerable and reversible toxicities during nelfinavir treatment in cancer patients, either as a monotherapy or in combination with chemo- or radiotherapy. Since orally available nelfinavir has been a safe drug of choice for both adult and pediatric HIV-infected patients for over two decades, exploiting its anti-cancer off-target effects will enable fast-tracking this newer option into the existing repertoire of cancer chemotherapeutics.

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Section: Potential Mechanisms Whereby Nelfinavir Exert Its Anti-casupporting

confidence: 55%

Section: Potential Mechanisms Whereby Nelfinavir Exert Its Anti-camentioning

confidence: 99%

The Anti-Cancer Properties of the HIV Protease Inhibitor Nelfinavir

Subeha

Telleria

2020

Cancers

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“…In vitro studies have suggested that some PIs might have anti-tumour effects against cervical cancer cells. 39,40 However, as the treatment allocation was not randomized in our study, this finding should be interpreted with caution.…”

Section: Discussionmentioning

confidence: 77%

Cervical cancer risk and impact of Pap‐based screening in HIV‐positive women on antiretroviral therapy in Johannesburg, South Africa

et al. 2017

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Data on invasive cervical cancer (ICC) incidence in HIV-positive women and the effect of cervical cancer screening in sub-Saharan Africa are scarce. We estimated i) ICC incidence rates in women (≥18 years) who initiated antiretroviral therapy (ART) at the Themba Lethu Clinic (TLC) in Johannesburg, South Africa, between 2004–2011; and ii) the effect of a Pap-based screening program. We included 10,640 women; median age at ART initiation: 35 years (interquartile range [IQR] 30–42), median CD4 count at ART initiation: 113 cells/μl (IQR 46–184). During 27,257 person-years (pys), 138 women were diagnosed with ICC; overall incidence rate: 506/100,000 pys (95% CI 428–598). The ICC incidence rate was highest (615/100,000 pys) in women who initiated ART before cervical cancer screening became available in 04/2005, and was lowest (260/100,000 pys) in women who initiated ART from 01/2009 onwards when the cervical cancer screening program and access to treatment of cervical lesions was expanded (adjusted hazard ratio [aHR] 0.42, 95% confidence interval [CI] 0.20–0.87). Advanced HIV/AIDS stage (4 versus 1, aHR 1.95, 95% CI 1.17–3.24) and middle age at ART initiation (36–45 versus 18–25 years, aHR 2.51, 95% CI 1.07–5.88) were risk factors for ICC. The ICC incidence rate substantially decreased with the implementation of a Pap-based screening program and improved access to treatment of cervical lesions. However, the risk of developing ICC after ART initiation remained high. To inform and improve ICC prevention and care for HIV-positive women in sub-Saharan Africa, implementation and monitoring of cervical cancer screening programs are essential.

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“…Although there is not yet published literature to support protease inhibitor treatment for anal cancer, protease inhibitors were shown to be effective in the treatment of HPV-induced head, neck, and cervical cancers through decreasing carcinogenesis and as a radiosensitizer. [12][13][14] Research supports that saquinavir functions by inhibiting HPV-associated oncoprotein E6, thus preventing E6-mediated inhibition of tumor suppressor gene p53. 5,6 Strengths of this study include the use of an already Food and Drug Administration-approved drug, saquinavir, in our research.…”

Section: Discussionmentioning

confidence: 99%

The Use of the Protease Inhibitor, Saquinavir, to Treat Anal Cancer Spheroids Derived from HPV Transgenic Mice

Johnson

Gunder

Leverson

et al. 2023

Diseases of the Colon &Amp; Rectum

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BACKGROUND: Anal cancer is associated with highrisk human papillomavirus infection and oncoprotein expression. We have identified several protease inhibitors, used to treat HIV, that decrease oncogene expression. OBJECTIVE:The aim of this project is to determine whether saquinavir, a protease inhibitor, results in a treatment response in anal cancer spheroids.DESIGN: K14E6/E7 transgenic mice (n = 5), which express human papillomavirus 16 oncoproteins E6 and E7 in their epithelium, were treated topically at the anus with a carcinogen, 7,12-dimethylbenz [a] anthracene, to promote anal tumor growth. Tumors were excised and digested, and cells were plated. The tumor cells form 3D multicellular aggregates known as spheroids. SETTINGS:This study was performed in an American Association for Accreditation of Laboratory Animal Care-approved facility. INTERVENTIONS:Spheroids were placed in treatment groups: no treatment, vehicle (dimethyl sulfoxide), and 15 μM saquinavir. Spheroids were imaged immediately pretreatment and 24 hours posttreatment.MAIN OUTCOME MEASURES: Spheroid diameters were measured using ImageJ and mean percent reduction was calculated for each spheroid to determine treatment effect on spheroid growth. Analysis of variance using pairwise comparisons was performed with Fisher protected least significant difference tests. RESULTS:The no-treatment (n = 119 spheroids) and vehicle (n = 126 spheroids) groups demonstrated an increase in spheroid diameter during the treatment period. In contrast, spheroids treated with saquinavir (n = 151 spheroids) demonstrated a statistically significant percent reduction compared to the no-treatment (p < 0.0001) and vehicle (p = 0.002) groups.LIMITATIONS: A limitation of these data is that some human error is likely present given that images were analyzed by 3 different scientists.CONCLUSIONS: Saquinavir leads to a statistically significant percent reduction in mice anal tumor spheroid growth ex vivo compared to control groups. Protease inhibitor therapy may be an effective treatment or adjuvant therapy to the Nigro protocol to promote anal cancer tumor regression.

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Nelfinavir is effective against human cervical cancer cells in vivo: a potential treatment modality in resource-limited settings

Cited by 7 publications

References 43 publications

The Anti-Cancer Properties of the HIV Protease Inhibitor Nelfinavir

The Anti-Cancer Properties of the HIV Protease Inhibitor Nelfinavir

Cervical cancer risk and impact of Pap‐based screening in HIV‐positive women on antiretroviral therapy in Johannesburg, South Africa

The Use of the Protease Inhibitor, Saquinavir, to Treat Anal Cancer Spheroids Derived from HPV Transgenic Mice

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