Drug library screen reveals benzimidazole derivatives as selective cytotoxic agents for KRAS-mutant lung cancer

Shimomura, Iwao; Yokoi, Akira; Kohama, Isaku; Kumazaki, Minami; Tada, Yuji; Ochiya, Takahiro; Yamamoto, Yusuke

doi:10.1016/j.canlet.2019.03.002

Cited by 32 publications

(39 citation statements)

References 44 publications

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“…Supplementary Table 1 ( 4 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 ) summarizes the antitumorigenicity of benzimidazole anthelmintics on cancer cell lines. Benzimidazole anthelmintics inhibit the progression of cancer through a variety of mechanisms.…”

Section: Antitumorigenic Effects Of Benzimidazole Anthelmintics In Camentioning

confidence: 99%

“…The benzimidazole anthelmintics usually decreased signaling proteins related to cell proliferation and survival, such as phosphorylated (p)HER2/3, PI3K/protein kinase B (AKT), rapidly accelerated fibrosarcoma (a family of three serine/threonine-specific protein kinases) (RAF)/MEK/ERK, mTOR, and Ki-67. Interestingly, fenbendazole inhibited PI3K/AKT and RAF/MEK/ERK in Kirsten rat sarcoma viral oncogene homolog (KRAS)-mutant lung cancer cells but had no effects in KRAS-wild-type H-1650 lung cancer cells despite inhibited cell viability ( 53 ). Fenbendazole also had no effects on cell viability in some p53 mutant lung cancer cells ( 55 ).…”

Section: Antitumorigenic Effects Of Benzimidazole Anthelmintics In Camentioning

confidence: 99%

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The Antitumor Potentials of Benzimidazole Anthelmintics as Repurposing Drugs

2020

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The development of refractory tumor cells limits therapeutic efficacy in cancer by activating mechanisms that promote cellular proliferation, migration, invasion, metastasis, and survival. Benzimidazole anthelmintics have broad-spectrum action to remove parasites both in human and veterinary medicine. In addition to being antiparasitic agents, benzimidazole anthelmintics are known to exert anticancer activities, such as the disruption of microtubule polymerization, the induction of apoptosis, cell cycle (G2/M) arrest, anti-angiogenesis, and blockage of glucose transport. These antitumorigenic effects even extend to cancer cells resistant to approved therapies and when in combination with conventional therapeutics, enhance anticancer efficacy and hold promise as adjuvants. Above all, these anthelmintics may offer a broad, safe spectrum to treat cancer, as demonstrated by their long history of use as antiparasitic agents. The present review summarizes central literature regarding the anticancer effects of benzimidazole anthelmintics, including albendazole, parbendazole, fenbendazole, mebendazole, oxibendazole, oxfendazole, ricobendazole, and flubendazole in cancer cell lines, animal tumor models, and clinical trials. This review provides valuable information on how to improve the quality of life in patients with cancers by increasing the treatment options and decreasing side effects from conventional therapy.

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Section: Antitumorigenic Effects Of Benzimidazole Anthelmintics In Camentioning

confidence: 99%

Section: Antitumorigenic Effects Of Benzimidazole Anthelmintics In Camentioning

confidence: 99%

The Antitumor Potentials of Benzimidazole Anthelmintics as Repurposing Drugs

2020

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“…Because of the structural similarities of benzimidazoles with purine, they can easily interact with the biomolecules of living systems. Therefore, they have considerable potential for use in medicinal chemistry and are a critical pharmacophore in drug discovery [5,6,7].…”

Section: Introductionmentioning

confidence: 99%

Design and Synthesis of Benzimidazole-Chalcone Derivatives as Potential Anticancer Agents

Hsieh

Chang

et al. 2019

Molecules

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Numerous reports have shown that conjugated benzimidazole derivatives possess various kinds of biological activities, including anticancer properties. In this report, we designed and synthesized 24 new molecules comprising a benzimidazole ring, arene, and alkyl chain-bearing cyclic moieties. The results showed that the N-substituted benzimidazole derivatives bearing an alkyl chain and a nitrogen-containing 5- or 6-membered ring enhanced the cytotoxic effects on human breast adenocarcinoma (MCF-7) and human ovarian carcinoma (OVCAR-3) cell lines. Among the 24 synthesized compounds, (2E)-1-(1-(3-morpholinopropyl)-1H-benzimidazol-2 -yl)-3-phenyl-2-propen-1-one) (23a) reduced the proliferation of MCF-7 and OVCAR-3 cell lines demonstrating superior outcomes to those of cisplatin.

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“…Shimomura and colleagues recently investigated molecular targets for K-RAS-activated lung cancer in K-RAS-mutant and wild-type lung cancer cell lines using a drug library of 1271 small molecules, and identified the cytotoxic effects of benzimidazole derivatives on K-RAS-mutant lung cancer cells [19]. In addition, the most recent small-molecule inhibitor termed AMG 510 was presented at the 2019 American Society of Clinical Oncology (ASCO) Annual Meeting indicating its potential to become the first drug to successfully target a K-RAS mutation in patients.…”

Section: K-rasmentioning

confidence: 99%

Current Approaches in NSCLC Targeting K-RAS and EGFR

Aran

Omerovic

2019

IJMS

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The research and treatment of non-small cell lung cancer (NSCLC) have achieved some important advances in recent years. Nonetheless, the overall survival rates for NSCLC remain low, indicating the importance to effectively develop new therapies and improve current approaches. The understanding of the function of different biomarkers involved in NSCLC progression, survival and response to therapy are important for the development of early detection tools and treatment options. Epidermal growth factor receptor (EGFR) and Kirsten rat sarcoma viral oncogene homolog (K-RAS) are two of the main significant biomarkers for the management of NSCLC. Mutations in these genes were associated with development and response to therapies. For example, the use of small molecule tyrosine kinase (TK) inhibitors and immunotherapy has led to benefits in some, but not all patients with altered EGFR. In contrast, there is still no effective approved drug to act upon patients harbouring K-RAS mutations. In addition, K-RAS mutations have been associated with lack of activity of TK inhibitors. However, promising approaches aimed to inhibit mutant K-RAS are currently under study. Therefore, this review will discuss these approaches and also EGFR therapies, and hopefully, it will draw attention to the need of continued research in the field in order to improve the outcomes in NSCLC patients.

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Drug library screen reveals benzimidazole derivatives as selective cytotoxic agents for KRAS-mutant lung cancer

Cited by 32 publications

References 44 publications

The Antitumor Potentials of Benzimidazole Anthelmintics as Repurposing Drugs

The Antitumor Potentials of Benzimidazole Anthelmintics as Repurposing Drugs

Design and Synthesis of Benzimidazole-Chalcone Derivatives as Potential Anticancer Agents

Current Approaches in NSCLC Targeting K-RAS and EGFR

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