Thatikonda Sowjanya, Chaudhary Ritu, Meshkovska Yeva, Biernacki Maria, Slebos Robbert J C, Song Xiaofei, Hall MacLean S, Lilley Kenneth, Pilon-Thomas Shari, Guevara-Patino Jose A, Spiess Philippe E, Chahoud Jad, Amelio Antonio L, Wachter Eric A, Rodrigues Dominic, Chung Christine H
Moffitt Cancer Center, United States.
Moffitt Cancer Center, Tampa, FL, United States.
Mol Cancer Ther. 2025 Jun 24. doi: 10.1158/1535-7163.MCT-24-0218.
Primary risk factors of head and neck squamous cell carcinoma (HNSCC) include human papillomavirus (HPV) infection and exposure to tobacco and excessive alcohol. Despite currently available treatments, patients with recurrent HNSCC still have poor survival, highlighting the need for innovative therapies. PV-10, also known as rose bengal sodium (RBS, 4,5,6,7-tetrachloro-2',4',5',7'-tetraiodofluorescein disodium), is a small molecule being developed as an intralesional (IL) therapeutic agent, exhibiting substantial anti-tumor activity across diverse cancer types, but current knowledge regarding the molecular mechanisms involved in response to PV-10 remains limited. We evaluated the cytotoxic effects of PV-10 in HNSCC and explored its molecular mechanisms. In vitro, we found that PV-10 induced cytotoxicity in mEER and MTE-RAS cell lines, primarily by increasing the production of reactive oxygen species and leading to apoptosis through a caspase-dependent mechanism. Additionally, we observed that PV-10 treatment increased the release of damage-associated molecular pattern molecules such as HMGB1 and ATP and enhanced expression of calreticulin, HSP-70, and HSP-90 indicating potent immunogenic cell death (ICD). In vivo, IL PV-10 injections led to significant tumor regression in both mEER and MTE-Ras models. Complete responses (CR) were observed in 7 of 21 (33%) mice in mEER although no CR was observed in MTE-Ras. Our data suggests that one of the possible mechanisms by which PV-10 triggers ICD is by inducing endoplasmic reticulum stress, autophagy, and apoptosis. Our findings contribute to further understanding of the underlying mechanisms of PV-10 induced cytotoxicity and to develop future clinical trials in locally recurrent HNSCC.
头颈部鳞状细胞癌（HNSCC）的主要风险因素包括人乳头瘤病毒（HPV）感染以及接触烟草和过量饮酒。尽管目前有多种治疗方法，但复发性HNSCC患者的生存率仍然很低，这凸显了对创新疗法的需求。PV-10，也称为孟加拉玫瑰红钠（RBS，4,5,6,7-四氯-2',4',5',7'-四碘荧光素二钠），是一种正在开发的小分子病灶内（IL）治疗剂，在多种癌症类型中均表现出显著的抗肿瘤活性，但目前关于PV-10反应所涉及的分子机制的了解仍然有限。我们评估了PV-10对HNSCC的细胞毒性作用，并探索了其分子机制。在体外，我们发现PV-10在mEER和MTE-RAS细胞系中诱导细胞毒性，主要是通过增加活性氧的产生，并通过半胱天冬酶依赖性机制导致细胞凋亡。此外，我们观察到PV-10处理增加了损伤相关分子模式分子如HMGB1和ATP的释放，并增强了钙网蛋白、HSP-70和HSP-90的表达，表明其具有强大的免疫原性细胞死亡（ICD）。在体内，病灶内注射PV-10导致mEER和MTE-Ras模型中的肿瘤显著消退。在mEER模型的21只小鼠中有7只（33%）观察到完全缓解（CR），尽管在MTE-Ras模型中未观察到CR。我们的数据表明，PV-10触发ICD的一种可能机制是通过诱导内质网应激、自噬和细胞凋亡。我们的研究结果有助于进一步了解PV-10诱导细胞毒性的潜在机制，并为局部复发性HNSCC的未来临床试验提供依据。
