EAPB0203, a member of the imidazoquinoxaline family, inhibits growth and induces caspase-dependent apoptosis in T-cell lymphomas and HTLV-I–associated adult T-cell leukemia/lymphoma

Abstract

Imiquimod is an immune response modifier currently used as a topical treatment of genital warts, basal cell carcinoma, cutaneous metastasis of malignant melanoma, and vascular tumors. We developed more efficient killers from the same family of compounds that can induce apoptosis without the prominent proinflammatory response associated with imiquimod. Among these new products, tk;4EAPB0203, a member of the imidazo IntroductionImiquimod, the first member of the imidazoquinolone family, is an immune response modifier with potent antiviral and antitumor activity in vivo. This product is currently approved as a topical treatment of external genital warts caused by human papilloma virus. [1][2][3] Recent evidence suggests that imiquimod is also efficacious as a topical therapy for basal cell carcinoma, intraepidermal keratinocyte neoplasias, cutaneous metastasis of malignant melanoma, and vascular tumors. 4,5 Moreover, imiquimod applied systemically in animal experiments has proven efficacy in a variety of transplantable tumors, including colon carcinomas, melanomas, lung sarcomas, mammary carcinomas, and bladder carcinomas. [6][7][8] It has been shown that imiquimod exerts its antiviral and antitumor effects in vivo, primarily by stimulating both the innate and adaptive immune responses. Imiquimod effects are mediated by the secretion of proinflammatory cytokines, including interferon-␣, interferon gamma, interleukin 6, interleukin 12, and tumor necrosis factor-␣. 9 However, recent in vitro studies showed that imiquimod, at clinically achievable concentrations, directly induces apoptosis in malignant keratinocytes and malignant melanoma cells, in the absence of immune cells. Furthermore, melanoma cell lines derived from imiquimod-resistant cutaneous metastasis, were also resistant to imiquimod in vitro. Interestingly, normal primary human melanocytes are resistant to imiquimod. 10 However, because imiquimod induces a significant proinflammatory response and stimulates the production of proinflammatory cytokines that can exert deleterious effects, more efficient killers from the same family of compounds, which can induce apoptosis without a prominent proinflammatory response, are needed. In a previous study, we designed and analyzed a series of imidazo[1,2-a]quinoxalines, as possible imiquimod analogues. We found that, contrary to imiquimod, these imidazo[1,2-a]quinoxalines inhibit both the production and the effects of tumor necrosis factor-␣; hence, these imiquimod antagonists can be considered as potential anti-inflammatory drugs. 11 Among these new products, EAPB0203 exhibits an important cytotoxic activity in vitro and is 50 times more potent than imiquimod against a human melanoma cell line (G.M. et al, unpublished data, 2007).The retrovirus HTLV-I is the causative agent of adult T-cell leukemia/lymphoma (ATL), an aggressive malignancy of CD4 ϩ T lymphocytes. 12 ATL is preceded by oligoclonal expansions of HTLV-I-infected activated T cells 13 as a result of the viral transactivator protein Tax expression, whic...

The Use of TLR7 and TLR8 Ligands for the Enhancement of Cancer Immunotherapy

“…Treatment with EAPB0203, a member of the imidazoquinoxaline family, also induced growth inhibition and caspase-dependent apoptosis in a series of malignant T cells, but not in normal T cells. However, it is not yet clear whether the effects of imidazoquinoxalines are mediated via TLR7 and/or TLR8 [102]. In addition to direct induction of apoptosis, treatment with imidazoquinolines leads to infiltration of CTLs, NK cells, and DCs with cytotoxic potential, as described above.…”

Quantitation of imidazo[1,2‐a]quinoxaline derivatives in human and rat plasma using LC/ESI‐MS

“…We develop imidazo[1,2-a]quinoxaline drugs with interesting antitumoral activity against lymphoma [15] and melanoma [16]. On melanoma, the first lead compound (EAPB0203, IC 50 = 1.57 lM) has an in vitro activity 110 times higher than fotemustine (IC 50 = 173 lM) and 45 times higher than imiquimod (IC 50 = 70 lM) used as references [16].…”

“…EAPB0203 treatment significantly down-regulated the anti-apoptotic proteins c-IAP-1 and Bcl-XL, and resulted in a significant loss of mitochondrial membrane potential, cytoplasmic release of cytochrome c, and caspase dependent apoptosis. In addition, in HTLV-I transformed cells only, EAPB0203 treatment stabilized p21 and p53 proteins but had no effect on NF-KB activation [15].…”

“…Three chemical series have been synthesized [14]: i) the imidazo[1,2-a]quinoxalines, ii) the imidazo [1,5-a]quinoxalines, and iii) the pyrazolo [1,5-a]qui-noxalines. Among the imidazo [1,2-a]quinoxaline series, we recently demonstrated that one of these compounds (EAPB0203) induced inhibition of cell proliferation and apoptosis in HTLV-I transformed and HTLV-I-negative malignant T-cells as well in fresh adult T-cell leukaemia (ATL) cells [15]. This compound exhibits inhibition of cell proliferation, G2/M cell cycle arrest, and induction of apoptosis in HTLV-I transformed and HTLV-I negative malignant T-cells while normal resting or activated T lymphocytes are resistant.…”

Cellular and molecular effect of antitumor agents

“…Por otra parte, derivados de 3-aril-quinoxalinas-2-carbonitrilo fueron evaluados en las líneas celulares SMMC-7721, K562, KB, A549 y PC-3, mostrando actividad citotóxica e hipoxia, induciendo apoptosis en una vía dependiente de caspasas (Hu, Xia, Shangguan, Liu, Hu & Sheng, 2012). Otro compuesto derivado de la familia de imidazoquinoxalinas de importancia es el denominado EAPB0203 (figura 4), el cual inhibe el crecimiento en los linfomas de células T sin la respuesta pro-inflamatoria asociada a otros miembros de esta familia, mostrando inhibición de la proliferación celular, detención del ciclo celular en fase G2/M e inducción de apoptosis dependiente de caspasa y liberación de citocromo c (Moarbess et al, 2008).…”