An Insight into Drug Repositioning for the Development of Novel Anti-Cancer Drugs

Bhattarai, Deepak; Singh, Sarbijt; Jang, Yerin; Han, Seung Hyeon; Lee, Kyeong; Choi, Yongseok

doi:10.2174/1568026616666160216153618

Cited by 25 publications

(22 citation statements)

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“…Developing a new chemical entity drug and delivering it to the market, known as de novo drug discovery, is a time-consuming and expensive process with increasing regulatory requirements and a high risk of failure-all of which could make the pharmaceutical industry a less desirable choice for investors. Nowadays, drug repurposing has become a successful strategy to fast-track therapeutic agents for the treatment of several emerging or rare diseases, such as AIDS, Alzheimer's disease and cancer [10,[34][35][36][37][38][39][40], but also infections with multidrug-resistant strains of clinically relevant pathogens [9,[41][42][43][44].…”

Section: Discussionmentioning

confidence: 99%

Repurposing Dihydropyridines for Treatment of Helicobacter pylori Infection

et al. 2019

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Antibiotic resistance is a major cause of the increasing failures in the current eradication therapies against Helicobacter pylori. In this scenario, repurposing drugs could be a valuable strategy to fast-track novel antimicrobial agents. In the present study, we analyzed the inhibitory capability of 1,4-dihydropyridine (DHP) antihypertensive drugs on the essential function of the H. pylori response regulator HsrA and investigated both the in vitro antimicrobial activities and the in vivo efficacy of DHP treatments against H. pylori. Six different commercially available and highly prescribed DHP drugs—namely, Nifedipine, Nicardipine, Nisoldipine, Nimodipine, Nitrendipine, and Lercanidipine—noticeably inhibited the DNA binding activity of HsrA and exhibited potent bactericidal activities against both metronidazole- and clarithromycin-resistant strains of H. pylori, with minimal inhibitory concentration (MIC) values in the range of 4 to 32 mg/L. The dynamics of the decline in the bacterial counts at 2 × MIC appeared to be correlated with the lipophilicity of the drugs, suggesting different translocation efficiencies of DHPs across the bacterial membrane. Oral treatments with 100 mg/kg/day of marketed formulations of Nimodipine or Nitrendipine in combination with omeprazole significantly reduced the H. pylori gastric colonization in mice. The results presented here support a novel therapeutic solution for treatment of antibiotic-resistant H. pylori infections.

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Section: Discussionmentioning

confidence: 99%

Repurposing Dihydropyridines for Treatment of Helicobacter pylori Infection

et al. 2019

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“…With this background, drug repositioning has emerged as a new concept in which an existing drug is used for a different disease. Such a drug is already known to be safe and to have appropriate pharmacokinetics in humans, and thus can be used for another disease with markedly less research time and cost compared to conventional drug development [ 4 ].…”

Section: Introductionmentioning

confidence: 99%

Drug repositioning of mevalonate pathway inhibitors as antitumor agents for ovarian cancer

et al. 2017

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Drug repositioning is an alternative strategy redirecting existing drugs for new disease. We have previously reported an antitumor effect of statins, antidyslipidemic drugs, on ovarian cancer in vitro and in vivo. In this study, we investigated the antitumor effects of other mevalonate pathway inhibitors and the mechanism of the antitumor effect from a metabolic perspective.The effects of inhibitors of the mevalonate pathway on tumor cell growth were evaluated in vitro. Bisphosphonates that inhibit this pathway are commonly used as antiosteoporotic drugs, and antitumor effects of the bisphosphonate were examined in vitro and in vivo. Metabolites in SKOV3 ovarian cancer cells were analyzed before and after lovastatin treatment, using capillary electrophoresis-mass spectrometry.All mevalonate pathway inhibitors showed concentration-dependent inhibitory effects on tumor cell growth. Particularly marked effects were obtained with inhibitors of farnesyltransferase and geranylgeranyltransferase. The bisphosphonate was also shown to have an antitumor effect in vivo. The expression of autophagy marker LC3A/3B was increased in cells after treatment. In metabolomics analysis, lovastatin treatment increased the metabolites involved in the tricarboxylic acid cycle while reducing the metabolites associated with glycolysis. Also it decreased glutathione and resulted to work with chemotherapeutic agents synergistically.Inhibition at any point in the mevalonate pathway, and especially of farnesyl pyrophosphate and geranylgeranyl pyrophosphate, suppresses growth of ovarian cancer cells. Inhibition of this pathway may induce autophagy, cause a shift to activation of the tricarboxylic acid cycle and enhance susceptibility to chemotherapy. Drug repositioning targeting mevalonate pathway for ovarian cancer deserves consideration for clinical application.

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“…In addition, a 168-bp fragment located at þ171/þ338 was amplified on the same precipitated samples as qualitative control. (24). In this context, several AEDs have shown anticancer activity, influencing cell growth and apoptosis in several cancer cell types in vitro (4, 6).…”

Section: Discussionmentioning

confidence: 99%

FoxO3a Mediates the Inhibitory Effects of the Antiepileptic Drug Lamotrigine on Breast Cancer Growth

Pellegrino

Rizza

Nigro

et al. 2018

Molecular Cancer Research

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Breast cancer is a complex and heterogeneous disease, with distinct histologic features dictating the therapy. Although the clinical outcome of breast cancer patients has been considerably improved, the occurrence of resistance to common endocrine and chemotherapy treatments remains the major cause of relapse and mortality. Thus, efforts in identifying new molecules to be employed in breast cancer therapy are needed. As a "faster" alternative to reach this aim, we evaluated whether lamotrigine, a broadly used anticonvulsant, could be "repurposed" as an antitumoral drug in breast cancer. Our data show that lamotrigine inhibits the proliferation, the anchorage-dependent, and independent cell growth in breast cancer cells (BCC), including hormone-resistant cell models. These effects were associated with cell-cycle arrest and modulation of related proteins (cyclin D1, cyclin E, p27, and p21), all target genes of FoxO3a, an ubiquitous transcription factor negatively regulated by AKT. Lamotrigine also increases the expression of another FoxO3a target, PTEN, which, in turn, downregulates the PI3K/Akt signaling pathway, with consequent dephosphorylation, thus activation, of FoxO3a. Moreover, lamotrigine induces FoxO3a expression by increasing its transcription through FoxO3a recruitment on specific FHRE located on its own promoter, in an autoregulatory fashion. Finally, lamotrigine significantly reduced tumor growth , increasing FoxO3a expression. The anticonvulsant drug lamotrigine shows strong antiproliferative activity on breast cancer, both and Thus, drug repurposing could represent a valuable option for a molecularly targeted therapy in breast cancer patients. .

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An Insight into Drug Repositioning for the Development of Novel Anti-Cancer Drugs

Cited by 25 publications

References 0 publications

Repurposing Dihydropyridines for Treatment of Helicobacter pylori Infection

Repurposing Dihydropyridines for Treatment of Helicobacter pylori Infection

Drug repositioning of mevalonate pathway inhibitors as antitumor agents for ovarian cancer

FoxO3a Mediates the Inhibitory Effects of the Antiepileptic Drug Lamotrigine on Breast Cancer Growth

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