Clonal Expansion of T Cells in Abdominal Aortic Aneurysm:  A Role for Doxycycline as Drug of Choice?

Kroon, A.M.; Taanman, Jan‐Willem

doi:10.3390/ijms160511178

Cited by 12 publications

(5 citation statements)

References 105 publications

(86 reference statements)

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“…We have argued that the serum and tissue levels of tetracycline analogs obtained with standard medication will not be sufficient to affect MMPs. Instead, we think that the obtained results should be interpreted to be caused by inhibition of clonal cell proliferation [ 25 , 26 ].…”

Section: Introductionmentioning

confidence: 99%

Mitochondria as oncotarget: a comparison between the tetracycline analogs doxycycline and COL-3

2018

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Tetracyclines have anticancer properties in addition to their well-known antibacterial properties. It has been proposed that tetracyclines slow metastasis and angiogenesis through inhibition of matrix metalloproteinases. However, we believe that the anticancer effect of tetracyclines is due to their inhibition of mitochondrial protein synthesis, resulting in a decrease of the mitochondrial energy generating capacity. Several groups have developed analogs that are void of antibacterial action. An example is COL-3, which is currently tested for its anticancer effects in clinical trials. We have undertaken a comparative study of the tetracycline analogs COL-3 and doxycycline, which has an antibacterial function, to further investigate the role of the mitochondrial energy generating capacity in the anticancer mechanism and, thereby, evaluate the usefulness of mitochondria as an oncotarget. Our experiments with cultures of the human A549, COLO357 and HT29 cancer cells and fibroblasts indicated that COL-3 is significantly more cytotoxic than doxycycline. Mitochondrial translation assays demonstrated that COL-3 has retained its inhibitory effect on mitochondrial protein synthesis. Both drugs caused a severe decrease in the levels of mitochondrially encoded cytochrome-c oxidase subunits and cytochrome-c oxidase activity. In addition, COL-3 produced a marked drop in the level of nuclear-encoded succinate dehydrogenase subunit A and citrate synthase activity, indicating that COL-3 has multiple inhibitory effects. Contrary to COL-3, the anticancer action of doxycycline appears to be based specifically on inhibition of mitochondrial protein synthesis, which is thought to affect rapidly proliferating cancer cells more than healthy tissue. Doxycycline is likely to cause less side effects that COL-3.

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Section: Introductionmentioning

confidence: 99%

Mitochondria as oncotarget: a comparison between the tetracycline analogs doxycycline and COL-3

2018

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“…The identification of the three components of the trimolecular complex in AAA, and in particular the clonal expansions of the α- and β-chain TCR of T cells in AAA lesions ([10, 41], and this study), the association of AAA with MHC Class I and II [20–22] and the identification of putative AAA antigens [23–36], provide a compelling argument that AAA is a specific antigen-driven T-cell disease. AAA formation is controlled by cells, cytokines, and small molecules that inhibit inflammation (Table 1, [86]). Impaired immunoregulation may also play a role [38–40].…”

Section: Discussionmentioning

confidence: 99%

Clonally expanded alpha-chain T-cell receptor (TCR) transcripts are present in aneurysmal lesions of patients with Abdominal Aortic Aneurysm (AAA)

White

Judy

et al. 2019

PLoS ONE

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Abdominal aortic aneurysm (AAA) is a life-threatening immunological disease responsible for 1 to 2% of all deaths in 65 year old or older individuals. Although mononuclear cell infiltrates have been demonstrated in AAA lesions and autoimmunity may be responsible for the initiation and account for the propagation of the disease, the information available about the pathogenesis of AAA is limited. To examine whether AAA lesions from patients with AAA contain clonally expanded α-chain TCR transcripts, we amplified by the non-palindromic adaptor-PCR (NPA-PCR)/Vα-specific PCR and/or the Vα-specific PCR these α-chain TCR transcripts. The amplified transcripts were cloned and sequenced. Substantial proportions of identical α-chain TCR transcripts were identified in AAA lesions of 4 of 5 patients, demonstrating that clonally expanded T cells are present in these AAA lesions. These results were statistically significant by the bimodal distribution. Three of 5 of these patients were typed by DNA-based HLA-typing and all three expressed DRB1 alleles containing the DRβGln70 amino acid residue that has been demonstrated to be associated with AAA. All three patients exhibited clonally expanded T cells in AAA lesions. Four of the 5 patients with AAA who exhibited clonal expansions of α-chain TCR transcripts, also exhibited clonal expansions of β-chain TCR transcripts in AAA lesions, as we have demonstrated previously (J Immunol 192:4897, 2014). αβ TCR-expressing T cells infiltrating AAA lesions contain T-cell clones which have undergone proliferation and clonal expansion in vivo in response to as yet unidentified specific antigens that may be self or nonself. These results provide additional evidence supporting the hypothesis that AAA is a specific antigen-driven T-cell autoimmune disease.

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“…Abdul-Hussien et al found 100 mg daily reduced AAA inflammation [25]. Recently, Kroom and Taanman [43] suggested doxycycline may inhibit clonal expansion of T-cells, and once a day dosing leads to troughs in doxycycline levels that reduce this effect. Unlike previous human AAA studies, we are measuring plasma doxycycline levels.…”

Section: Discussionmentioning

confidence: 99%

Non-invasive Treatment of Abdominal Aortic Aneurysm Clinical Trial (N-TA 3 CT): Design of a Phase IIb, placebo-controlled, double-blind, randomized clinical trial of doxycycline for the reduction of growth of small abdominal aortic aneurysm

Baxter

Matsumura

Curci

et al. 2016

Contemporary Clinical Trials

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Objectives The Non-Invasive Treatment of Abdominal Aortic Aneurysm Clinical Trial (N-TA3CT) is a Phase IIb randomized, placebo-controlled clinical trial, testing doxycycline (100 mg bid) for inhibition of growth in the greatest transverse, orthogonal diameter of small abdominal aortic aneurysms (AAA). Methods We will enroll 258 patients, ≥ 55 years of age who have AAA, men: 3.5–5.0 cm and women: 3.5–4.5 cm on CT scans confirmed centrally. The primary outcome is growth in maximal transverse, orthogonal diameter from baseline to 24-month follow-up. Secondary analyses address doxycycline effects on clinical events, aneurysm volume, and biomarkers. Primary analysis will be performed according to the principle of intention-to-treat accounting for death and ruptures by use of normal scores in analysis of covariance. At the time of the data file reported, 200 subjects have been randomized. We started enrollment in mid-2013 and will complete enrollment by mid-2016. Results Participant average age = 70.9 years, (SD = 7.6 years) and maximum transverse diameter = 4.3 cm for men (SD = 0.4) and 4.0 cm for women (SD = 0.3). Conclusion N-TA3CT is a critical experiment to determine whether doxycycline reduces growth of small AAA and systemic markers of inflammation previously seen in bench experiments and observational human studies to be associated with AAA growth. Our patient population baseline measurements agree with the design assumptions supporting our expectation of 90% power or greater to reject a null hypothesis in favor of an alternative hypothesis when growth is reduced by at least 40%. Registration: clinicaltrials.gov #NCT01756833.

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Clonal Expansion of T Cells in Abdominal Aortic Aneurysm: A Role for Doxycycline as Drug of Choice?

Cited by 12 publications

References 105 publications

Mitochondria as oncotarget: a comparison between the tetracycline analogs doxycycline and COL-3

Mitochondria as oncotarget: a comparison between the tetracycline analogs doxycycline and COL-3

Clonally expanded alpha-chain T-cell receptor (TCR) transcripts are present in aneurysmal lesions of patients with Abdominal Aortic Aneurysm (AAA)

Non-invasive Treatment of Abdominal Aortic Aneurysm Clinical Trial (N-TA 3 CT): Design of a Phase IIb, placebo-controlled, double-blind, randomized clinical trial of doxycycline for the reduction of growth of small abdominal aortic aneurysm

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