Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.
ADVANCED SEARCH
Log in
Top
BMC Medicine
Published in: BMC Medicine 1/2022

Open Access 01-12-2022 | Chronic Inflammatory Bowel Disease | Research article

Proguanil and atovaquone use is associated with lower colorectal cancer risk: a nationwide cohort study

Authors: Naiqi Zhang, Jan Sundquist, Kristina Sundquist, Jianguang Ji

Published in: BMC Medicine | Issue 1/2022

Login to get access

Abstract

Background

Individuals with a family history of colorectal cancer (CRC) are at a high risk of developing CRC. Preclinical studies suggest that the anti-malaria drug proguanil and atovaquone might play a role in preventing CRC, but population-based evidence is still lacking.

Methods

By accessing a couple of nationwide Swedish registers, we performed a cohort study to explore whether using proguanil and atovaquone might associate with a lower risk of CRC by adopting a new-user study design. Adults who have 1 or more first-degree relatives (parents or siblings) diagnosed with CRC were identified and linked with the Prescribed Drug Register to evaluate their administration history of proguanil and atovaquone. Survival analysis of the time to CRC diagnosis with Cox proportional hazards regression was used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs).

Results

A total of 16,817 incident proguanil/atovaquone users were identified and matched with 168,170 comparisons, who did not use proguanil/atovaquone, on the ratio of 1:10. We found a significant negative association between proguanil/atovaquone use and risk of CRC (adjusted HR, 0.76; 95% CI, 0.62–0.93). Test for trend showed significant dose- and duration-response correlations (P < 0.001). The association was more pronounced in CRC diagnosed at an advanced stage than at an early stage (adjusted HR, 0.69 vs.0.81).

Conclusions

This national-wide population-based cohort study showed that the use of proguanil and atovaquone was associated with a reduced risk of CRC among individuals with a family history of CRC.
Appendix
Available only for authorised users
Literature
1.
Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018;68(6):394–424.CrossRefPubMed
2.
Global Burden of Disease Cancer C, Fitzmaurice C, Abate D, Abbasi N, Abbastabar H, Abd-Allah F, et al. Global, regional, and national cancer incidence, mortality, years of life lost, years lived with disability, and disability-adjusted life-years for 29 cancer groups, 1990 to 2017: a systematic analysis for the global burden of disease study. JAMA Oncol. 2019;5(12):1749–68.
3.
4.
Lichtenstein P, Holm NV, Verkasalo PK, Iliadou A, Kaprio J, Koskenvuo M, et al. Environmental and heritable factors in the causation of cancer--analyses of cohorts of twins from Sweden, Denmark, and Finland. N Engl J Med. 2000;343(2):78–85.CrossRefPubMed
5.
Johns LE, Houlston RS. A systematic review and meta-analysis of familial colorectal cancer risk. Am J Gastroenterol. 2001;96(10):2992–3003.CrossRefPubMed
6.
Johnson CM, Wei C, Ensor JE, Smolenski DJ, Amos CI, Levin B, et al. Meta-analyses of colorectal cancer risk factors. Cancer Causes Control. 2013;24(6):1207–22.CrossRefPubMedPubMedCentral
7.
8.
Kathuria D, Raul AD, Wanjari P, Bharatam PV. Biguanides: species with versatile therapeutic applications. Eur J Med Chem. 2021;219:113378.CrossRefPubMed
9.
Lv Z, Guo Y. Metformin and its benefits for various diseases. Front Endocrinol (Lausanne). 2020;11:191.CrossRef
10.
Barbieri F, Verduci I, Carlini V, Zona G, Pagano A, Mazzanti M, et al. Repurposed biguanide drugs in glioblastoma exert antiproliferative effects via the inhibition of intracellular chloride channel 1 activity. Front Oncol. 2019;9:135.CrossRefPubMedPubMedCentral
11.
Lea MA, Kim H, des BC. Effects of biguanides on growth and glycolysis of bladder and colon cancer cells. Anticancer Res. 2018;38(9):5003–11.CrossRefPubMed
12.
Xiao D, Lu Z, Wang Z, Zhou S, Cao M, Deng J, et al. Synthesis, biological evaluation and anti-proliferative mechanism of fluorine-containing proguanil derivatives. Bioorg Med Chem. 2020;28(2):115258.CrossRefPubMed
13.
Fiorillo M, Lamb R, Tanowitz HB, Mutti L, Krstic-Demonacos M, Cappello AR, et al. Repurposing atovaquone: targeting mitochondrial complex III and OXPHOS to eradicate cancer stem cells. Oncotarget. 2016;7(23):34084–99.CrossRefPubMedPubMedCentral
14.
15.
Ji J, Sundquist J, Sundquist K. Cholera vaccine use is associated with a reduced risk of death in patients with colorectal cancer: a population-based study. Gastroenterology. 2018;154(1):86–92 e1.CrossRefPubMed
16.
17.
Quan H, Li B, Couris CM, Fushimi K, Graham P, Hider P, et al. Updating and validating the Charlson comorbidity index and score for risk adjustment in hospital discharge abstracts using data from 6 countries. Am J Epidemiol. 2011;173(6):676–82.CrossRefPubMed
18.
Chen CC, Basch CE, Yamada T. An evaluation of colonoscopy use: implications for health education. J Cancer Educ. 2010;25(2):160–5.CrossRefPubMed
19.
Kerber RA, Neklason DW, Samowitz WS, Burt RW. Frequency of familial colon cancer and hereditary nonpolyposis colorectal cancer (Lynch syndrome) in a large population database. Familial Cancer. 2005;4(3):239–44.CrossRefPubMed
20.
Taylor DP, Burt RW, Williams MS, Haug PJ, Cannon-Albright LA. Population-based family history-specific risks for colorectal cancer: a constellation approach. Gastroenterology. 2010;138(3):877–85.CrossRefPubMed
21.
Butterworth AS, Higgins JP, Pharoah P. Relative and absolute risk of colorectal cancer for individuals with a family history: a meta-analysis. Eur J Cancer. 2006;42(2):216–27.CrossRefPubMed
22.
23.
Bridges HR, Jones AJ, Pollak MN, Hirst J. Effects of metformin and other biguanides on oxidative phosphorylation in mitochondria. Biochem J. 2014;462(3):475–87.CrossRefPubMed
24.
Ashton TM, Fokas E, Kunz-Schughart LA, Folkes LK, Anbalagan S, Huether M, et al. The anti-malarial atovaquone increases radiosensitivity by alleviating tumour hypoxia. Nat Commun. 2016;7:12308.CrossRefPubMedPubMedCentral
25.
Tharmalingham H, Hoskin P. Clinical trials targeting hypoxia. Br J Radiol. 2019;92(1093):20170966.PubMed
26.
Tian S, Chen H, Tan W. Targeting mitochondrial respiration as a therapeutic strategy for cervical cancer. Biochem Biophys Res Commun. 2018;499(4):1019–24.CrossRefPubMed
27.
Lv Z, Yan X, Lu L, Su C, He Y. Atovaquone enhances doxorubicin’s efficacy via inhibiting mitochondrial respiration and STAT3 in aggressive thyroid cancer. J Bioenerg Biomembr. 2018;50(4):263–70.CrossRefPubMed
28.
Chen D, Sun X, Zhang X, Cao J. Targeting mitochondria by anthelmintic drug atovaquone sensitizes renal cell carcinoma to chemotherapy and immunotherapy. J Biochem Mol Toxicol. 2018;32(9):e22195.CrossRefPubMed
29.
Force USPST. Routine aspirin or nonsteroidal anti-inflammatory drugs for the primary prevention of colorectal cancer: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med. 2007;146(5):361–4.CrossRef
30.
Dehmer SP, O'Keefe LR, Grossman ES, Maciosek MV. Aspirin use to prevent cardiovascular disease and colorectal cancer: an updated decision analysis for the U.S. Preventive Services Task Force. Rockville (MD): Agency for Healthcare Research and Quality (US). 2022. Report No.: 21-05283-EF-2.
31.
Boggild AK, Parise ME, Lewis LS, Kain KC. Atovaquone-proguanil: report from the CDC expert meeting on malaria chemoprophylaxis (II). Am J Trop Med Hyg. 2007;76(2):208–23.CrossRefPubMed
32.
33.
Abugroun A, Colina Garcia I, Ahmed F, Potts S, Flicker M. The first report of atovaquone/proguanil-induced vanishing bile duct syndrome: case report and mini-review. Travel Med Infect Dis. 2019;32:101439.
34.
Looareesuwan S, Chulay JD, Canfield CJ, Hutchinson DB. Malarone (atovaquone and proguanil hydrochloride): a review of its clinical development for treatment of malaria. Malarone Clinical Trials Study Group. Am J Trop Med Hyg. 1999;60(4):533–41.CrossRefPubMed
Metadata
Title
Proguanil and atovaquone use is associated with lower colorectal cancer risk: a nationwide cohort study
Authors
Naiqi Zhang
Jan Sundquist
Kristina Sundquist
Jianguang Ji
Publication date
01-12-2022
Publisher
BioMed Central
Published in
BMC Medicine / Issue 1/2022
Electronic ISSN: 1741-7015
DOI
https://doi.org/10.1186/s12916-022-02643-3

Other articles of this Issue 1/2022

BMC Medicine 1/2022 Go to the issue

Review

Severe acute hepatitis of unknown aetiology in children—what is known?

Research article

Proactive community case management decreased malaria prevalence in rural Madagascar: results from a cluster randomized trial

Editorial

Maternal factors during pregnancy influencing maternal, fetal, and childhood outcomes

Research article

Deep learning radiomics based on contrast-enhanced ultrasound images for assisted diagnosis of pancreatic ductal adenocarcinoma and chronic pancreatitis

Research article

Predictive validity of the Stopping Elderly Accidents, Deaths & Injuries (STEADI) program fall risk screening algorithms among community-dwelling Thai elderly

Research article

Effects of providing free hearing aids on multiple health outcomes among middle-aged and older adults with hearing loss in rural China: a randomized controlled trial