A Novel Combinatorial Regimen Using Sorafenib and Uttroside B, A US FDA-designated 'Orphan Drug', for the Treatment of Hepatocellular Carcinoma.

IF 2.6 4区 医学 Q3 CHEMISTRY, MEDICINAL
Chenicheri Kizhakkeveettil Keerthana, Sreekumar U Aiswarya, Tennyson P Rayginia, Yadu Vijayan, Shirly James, Sadiq C Shifana, Sankar Sundaram, D K Induja, Ravi S Lankalapalli, Kuzhuvelil B Harikumar, Ruby John Anto
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Abstract

Introduction: Sorafenib (Sor) is the first-line treatment option in clinics for treating advanced unresectable hepatocellular carcinoma (HCC). However, acquired chemoresistance and adverse side effects associated with Sor monotherapy limit its clinical benefits. We have previously reported the exceptional anti-HCC potential of uttroside B (Utt-B), a furostanol saponin isolated in our lab from Solanum nigrum Linn. leaves. The current study has evaluated the supremacy of a combinatorial regimen of Sor and Utt-B over Sor monotherapy.

Methods: MTT assay was used for In vitro cytotoxicity studies. A clonogenic assay was conducted to assess the anti-proliferative effect of the combination. Annexin V/PI staining, confocal microscopy, FACS cell cycle analysis, and Western blotting experiments were performed to validate the pro-apoptotic potential of the combination in HepG2 and Huh7 cell lines. Pharmacological safety evaluation was performed in Swiss albino mice.

Results: Our results indicate that Utt-B augments Sor-induced cytotoxicity in HepG2 and Huh7 cells. The combination inhibits the proliferation of liver cancer cells by inducing apoptosis through activation of the caspases 7 and 3, leading to PARP cleavage. Furthermore, the combination does not induce any acute toxicity in vivo, even at a dose five times that of the effective therapeutic dose.

Conclusion: Our results highlight the potential of Utt-B as an effective chemosensitizer, which can augment the efficacy of Sor against HCC and circumvent Sor-induced toxic side effects. Moreover, this is the first and only report to date on the chemosensitizing potential of Utt-B and the only report that demonstrates the therapeutic efficacy and pharmacological safety of a novel combinatorial regimen involving Utt-B and Sor for combating HCC.

使用索拉非尼和美国 FDA 指定的 "孤儿药 "Uttroside B 治疗肝细胞癌的新型联合疗法。
简介索拉非尼(Sorafenib,Sor)是治疗晚期不可切除肝细胞癌(HCC)的一线治疗方案。然而,与索拉非尼单药治疗相关的获得性化疗耐药性和不良副作用限制了其临床疗效。我们以前曾报道过乌头苷 B(Utt-B)具有非凡的抗 HCC 潜力,乌头苷 B 是我们实验室从黑茄科植物茄属(Solanum nigrum Linn.)叶片中分离出的一种呋喃甾醇皂甙。目前的研究评估了Sor和Utt-B组合疗法比Sor单药疗法的优越性:方法:采用 MTT 法进行体外细胞毒性研究。方法:MTT 试验用于体外细胞毒性研究,克隆生成试验用于评估联合疗法的抗增殖效果。进行了附件素 V/PI 染色、共聚焦显微镜、FACS 细胞周期分析和 Western 印迹实验,以验证组合药物在 HepG2 和 Huh7 细胞系中的促凋亡潜力。在瑞士白化小鼠中进行了药理安全性评估:结果:我们的研究结果表明,Utt-B能增强Sor诱导的HepG2和Huh7细胞的细胞毒性。通过激活 caspase 7 和 3,导致 PARP 分裂,从而诱导细胞凋亡,该组合抑制了肝癌细胞的增殖。此外,即使联合用药的剂量是有效治疗剂量的五倍,在体内也不会引起任何急性毒性:我们的研究结果凸显了 Utt-B 作为一种有效化疗增敏剂的潜力,它可以增强 Sor 对 HCC 的疗效,并避免 Sor 引起的毒副作用。此外,这是迄今为止第一份也是唯一一份关于 Utt-B 化疗增敏潜力的报告,也是唯一一份证明 Utt-B 和 Sor 联合治疗 HCC 的疗效和药理安全性的报告。
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来源期刊
Anti-cancer agents in medicinal chemistry
Anti-cancer agents in medicinal chemistry ONCOLOGY-CHEMISTRY, MEDICINAL
CiteScore
5.10
自引率
3.60%
发文量
323
审稿时长
4-8 weeks
期刊介绍: Formerly: Current Medicinal Chemistry - Anti-Cancer Agents. Anti-Cancer Agents in Medicinal Chemistry aims to cover all the latest and outstanding developments in medicinal chemistry and rational drug design for the discovery of anti-cancer agents. Each issue contains a series of timely in-depth reviews and guest edited issues written by leaders in the field covering a range of current topics in cancer medicinal chemistry. The journal only considers high quality research papers for publication. Anti-Cancer Agents in Medicinal Chemistry is an essential journal for every medicinal chemist who wishes to be kept informed and up-to-date with the latest and most important developments in cancer drug discovery.
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