Whang Sonia N, Rodarte Valeria, Lohman Trevor, Barforough Josh, Chitsike Lennox, Lucas Gina N, Lee David, Ruiz-Jimenez Caleb, Wongworawat Yan Chen, Ali-Fehmi Rouba, Wahidi Marya, Unternaehrer Juli, Filippov Valery, Duerksen-Hughes Penelope J
Department of Basic Science, School of Medicine, Loma Linda University, 11021 Campus Street, Alumni Hall 101, Loma Linda, CA, 92350, USA.
School of Allied Health Professions, Loma Linda University, Loma Linda, CA, 92350, USA.
BMC Cancer. 2025 Aug 1;25(1):1251. doi: 10.1186/s12885-025-14638-3.
Head and neck squamous cell carcinoma (HNSCC) affects more than half a million people annually, and nearly 80% of oropharyngeal cancer cases are caused by human papillomavirus (HPV). Current treatments include chemo- and radiotherapy, though the effectiveness of these therapies is limited by the viral oncoprotein E6, which disrupts apoptotic pathways by binding and accelerating the degradation of molecules such as E6AP and caspase-8. Our lab has identified an E6 inhibitor, 30-hydroxygambogic acid (GA-OH), that is able to maintain these apoptotic signaling molecules.
To further explore the therapeutic potential of this small molecule, we determined its antitumor efficacy in vivo. We developed an optimized xenograft model for HPV HNSCC, assessed GA-OH’s toxicity, and evaluated the effectiveness of GA-OH in combination with chemotherapy utilizing the optimized concentration of 0.6 mg/kg.
GA-OH significantly increases (* = 0.0105) cisplatin’s efficacy in HPV HNSCC in vivo without overt clinical manifestations. The only toxicities noted were a 4-fold increase in creatine kinase (**** < 0.0001) and a 2.4-fold increase in aspartate aminotransferase (** = 0.0057) in the cisplatin and GA-OH combination group compared to the vehicle group.
The small molecule GA-OH was tolerable in our murine model, significantly amplifying the efficacy of cisplatin treatment.
The online version contains supplementary material available at 10.1186/s12885-025-14638-3.
头颈部鳞状细胞癌（HNSCC）每年影响超过50万人，近80%的口咽癌病例由人乳头瘤病毒（HPV）引起。目前的治疗方法包括化疗和放疗，然而这些疗法的有效性受到病毒癌蛋白E6的限制，E6通过结合并加速E6相关蛋白（E6AP）和半胱天冬酶-8等分子的降解来破坏凋亡途径。我们实验室已鉴定出一种E6抑制剂，30-羟基藤黄酸（GA-OH），它能够维持这些凋亡信号分子。
为进一步探索这种小分子的治疗潜力，我们在体内确定了其抗肿瘤功效。我们建立了一种针对HPV-HNSCC的优化异种移植模型，评估了GA-OH的毒性，并利用0.6mg/kg的优化浓度评估了GA-OH与化疗联合使用的有效性。
GA-OH在体内显著提高了（* = 0.0105）顺铂对HPV-HNSCC的疗效，且无明显临床表现。与溶剂对照组相比，在顺铂和GA-OH联合治疗组中观察到的唯一毒性是肌酸激酶升高4倍（**** < 0.0001）和天冬氨酸转氨酶升高2.4倍（** = 0.0057）。
小分子GA-OH在我们的小鼠模型中耐受性良好，显著增强了顺铂治疗的疗效。
在线版本包含可在10.1186/s12885-025-14638-3获取的补充材料。
