In silico and in vitro screening for carcinogenic potential of angiotensin-converting enzyme inhibitors and their degradation impurities

Regulska, Katarzyna; Matera-Witkiewicz, Agnieszka; Mikołajczyk, Aleksandra; Stanisz, Beata

doi:10.1016/j.taap.2023.116541

Cited by 2 publications

(2 citation statements)

References 23 publications

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“…Its primary problem was a limited scope of application, which mainly covered new drugs submitted after 2014. Thus, older pharmaceuticals, such as ACE-Is and ARBs, remained unverified in the safety aspect in question [66][67][68][69]. Interestingly, for the pharmacologically allied ARBs, the suggestions on their potential carcinogenicity were available even before the nitrosamine crisis.…”

Section: Root Cause Of Concernmentioning

confidence: 99%

Angiotensin-converting enzyme inhibitors for ovarian cancer? — a new adjuvant option or a silent trap

Regulska,

Michalak,

Kolenda

et al. 2023

Rep Pract Oncol Radiother.

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Background Ovarian cancer is a huge therapeutic and financial problem for which approved treatments have already achieved their limit of efficiency. A cost-effective strategy to extend therapeutic options in this malignancy is drug repurposing aimed at overcoming chemoresistance. Here, angiotensin-converting enzyme inhibitors (ACE-I) are worth considering. Materials and methods We searched literature for publications supporting the idea of adjuvant application of ACE-Is in ovarian malignancy. Then, we searched The Cancer Genome Atlas databases for relevant alternations of gene expression patterns. We also performed in silico structure-activity relationship evaluation for predicting ACE-Is’ cytotoxicity against ovarian cancer cell lines. Finally, we reviewed the potential obstacles in ACE-Is repurposing process. Results The alternation of angiotensin receptor expression in ovarian cancer translates into poorer patient survival. This confirms the participation of the renin-angiotensin system in ovarian carcinogenesis. In observational studies, ACE-Is were shown synergize with both, platinum-based chemotherapy as well as with antiangiogenic therapy. Consistently, our in silico simulation showed that ACE-Is are probably cytotoxic against ovarian cancer cells. However, the publications on their chemopreventive properties were inconclusive. In addition, some reports correlated ACE-Is use with increased general cancer incidence. We hypothesized that this effect could be associated with mutagenic nitrosamine formation in ACE-Is’ pharmaceutical formulations, as was the case with angiotensin receptor blockers (ARBs) and other well-established pharmaceuticals. Conclusions Available data warrant further research into repositioning ACE-Is to ovarian cancer as chemosensitizers. Prior to this, however, a special research program is needed to detect possible genotoxic contaminants of ACE-Is.

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Section: Root Cause Of Concernmentioning

confidence: 99%

Angiotensin-converting enzyme inhibitors for ovarian cancer? — a new adjuvant option or a silent trap

Regulska,

Michalak,

Kolenda

et al. 2023

Rep Pract Oncol Radiother.

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“…Despite the unquestionable on-target efficiency, there are accumulating reports suggesting serious off-target toxicity of these drugs. Safety concerns, in particular, relate to their pro-carcinogenic potential, evidenced by increased incidence of malignancy among ACE-Is users [3,4]. Specifically, the risk regards common neoplastic conditions such as: endometrial [5,6], melanoma, kidney and female reproductive cancers [7][8][9][10][11].…”

Section: Introductionmentioning

confidence: 99%

Impact of ramipril nitroso-metabolites on cancer incidence — in silico and in vitro safety evaluation

Regulska,

Kolenda,

Michalak

et al. 2023

Rep Pract Oncol Radiother.

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Background Angiotensin-converting enzyme inhibitors (ACE-I) and their pharmacologically related sartans have been associated with an increased cancer incidence in several clinical observations. In 2018, sartans were revealed as being significantly contaminated with nitrosamines. Nitrosamines are potent human mutagens that can be formed ex vivo and, more concerningly, also in vivo from nitrosatable drug precursors. Their formation in sartans may justify the reported cancer risk and, by analogy, this may also apply to ACE-Is. Materials and methods We investigated a commonly used ACE-I, ramipril (RAM). We checked its susceptibility to in vivo interaction with nitrite, potentially resulting in the generation of mutagenic N-nitrosamines. To that end, in silico simulation of mutagenicity of RAM nitroso-derivatives was performed using VEGA-GUI software. Then, the Nitrosation Assay Procedure was conducted which served as a model of endogenous reaction. The resulting post-nitrosation mixtures were subjected to a bacterial reverse mutation test employing Salmonella typhimurium strains TA98 and TA100 with and without metabolic activation. Results Our results showed that studied samples did not induce point mutations in the test bacteria, regardless of the catalytic cytochrome activity. Conclusion We concluded that RAM endogenous nitrosation is not the reason for increased cancer incidence. However, other ACE-Is must be verified in a similar manner.

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In silico and in vitro screening for carcinogenic potential of angiotensin-converting enzyme inhibitors and their degradation impurities

Cited by 2 publications

References 23 publications

Angiotensin-converting enzyme inhibitors for ovarian cancer? — a new adjuvant option or a silent trap

Angiotensin-converting enzyme inhibitors for ovarian cancer? — a new adjuvant option or a silent trap

Impact of ramipril nitroso-metabolites on cancer incidence — in silico and in vitro safety evaluation

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