Rickard Brittany P, Sapienza-Lundie Lauren A, Overchuk Marta, Tan Xianming, Bae-Jump Victoria L, Yates Melinda S, Fenton Suzanne E, Rizvi Imran
Department of Biological Sciences, North Carolina State University, Raleigh, North Carolina, USA.
Curriculum in Toxicology and Environmental Medicine, University of North Carolina School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
Photochem Photobiol. 2025 Mar 10. doi: 10.1111/php.14073.
First-line treatment for advanced-stage or recurrent endometrial cancer consists of platinum- and taxane-based chemotherapy, to which many patients will develop resistance. Determining the factors that contribute to platinum resistance and developing alternate treatment options for patients with advanced-stage gynecologic malignancies is critical to improving survival outcomes. Recently, we published the first study evaluating the contribution of perfluoroalkyl substances (PFAS) exposure to platinum resistance in endometrial cancer cell lines and found that select PFAS induce carboplatin resistance, potentially by dysregulating mitochondrial function. The present study expands upon those findings by examining the efficacy of photodynamic priming (PDP) in combination with carboplatin to overcome PFAS-induced platinum resistance. Due to the suspected role of mitochondrial dysfunction in platinum resistance, two clinically approved photosensitizers that, in part, localize to mitochondrial membranes or are synthesized in mitochondria were evaluated: benzoporphyrin derivative (BPD) and aminolevulinic acid-induced protoporphyrin IX (ALA-PpIX), respectively. Combination of ALA-PpIX-mediated PDP + carboplatin resulted in a greater reduction in survival fraction than the same combination with BPD. While PDP with both photosensitizers reduced mitochondrial membrane potential, the reduction was greater with BPD-PDP than ALA-PpIX-PDP. These findings demonstrate that BPD-PDP and ALA-PpIX-PDP in combination with carboplatin can be used to overcome PFAS-induced platinum resistance in endometrial cancer cells.
晚期或复发性子宫内膜癌的一线治疗方案为铂类与紫杉烷类联合化疗，但许多患者会对此产生耐药性。确定导致铂类耐药的因素并为晚期妇科恶性肿瘤患者开发替代治疗方案对于改善生存结局至关重要。最近，我们发表了首项评估全氟烷基物质（PFAS）暴露对子宫内膜癌细胞系铂类耐药性影响的研究，发现某些PFAS可诱导卡铂耐药，可能是通过线粒体功能失调来实现的。本研究通过检验光动力预激发（PDP）联合卡铂克服PFAS诱导的铂类耐药性的疗效，对上述发现进行了拓展。鉴于线粒体功能障碍在铂类耐药中可能发挥的作用，我们评估了两种临床批准的光敏剂：分别为部分定位于线粒体膜或在线粒体内合成的苯并卟啉衍生物（BPD）和氨基乙酰丙酸诱导的原卟啉IX（ALA-PpIX）。与BPD联合使用相比，ALA-PpIX介导的PDP联合卡铂可使存活分数降低得更多。虽然两种光敏剂介导的PDP均可降低线粒体膜电位，但BPD-PDP组的降低幅度大于ALA-PpIX-PDP组。这些发现表明，BPD-PDP和ALA-PpIX-PDP联合卡铂可用于克服子宫内膜癌细胞中PFAS诱导的铂类耐药性。
