Kabagwira Janviere, Fuller Ryan N, Vallejos Paul A, Sugiono Chase S, Andrianarijaona Vola-Masoandro, Chism Jazmine Brianna, O'Leary Michael P, Molina David Caba, Langridge William, Senthil Maheswari, Wall Nathan R
Department of Basic Science, Division of Biochemistry, Loma Linda University, Loma Linda, CA, USA.
Center for Health Disparities and Molecular Medicine, Loma Linda University, Loma Linda, CA, USA.
Onco Targets Ther. 2024 Jan 30;17:63-78. doi: 10.2147/OTT.S448024. eCollection 2024.
Peritoneal metastases from colorectal cancer (CRC) present a significant clinical challenge with poor prognosis, often unresponsive to systemic chemotherapy. Cytoreductive surgery (CRS) combined with hyperthermic intraperitoneal chemotherapy (HIPEC) is a treatment approach for select patients. The use of curcumin, a natural compound with antitumor properties, in HIPEC is of interest due to its lower side effects compared to conventional drugs and potential for increased efficacy through direct delivery to the peritoneal cavity.
An in vitro hyperthermic model was developed to simulate clinical HIPEC conditions. Three colon cancer cell lines (SK-CO-1, COLO205, SNU-C1) representing different genetic mutations (p53, KRAS, BRAF) were treated with either curcumin (25 µM) or mitomycin-C (1 µM) for 1, 2, or 3 hours. Post-treatment, cells were incubated at 37°C (normothermia) or 42°C (hyperthermia). Cell viability and proliferation were assessed at 24, 48 and 72 hours post-treatment using Annexin V/PI, MTT assay, trypan blue exclusion, and Hoffman microscopy.
Hyperthermia significantly enhanced the antitumor efficacy of curcumin, evidenced by a two-fold reduction in cell viability compared to normothermia across all cell lines. In the SNU-C1 cell line, which harbors a p53 mutation, mitomycin-C failed to significantly impact cell viability, unlike curcumin, suggesting mutation-specific differences in treatment response.
The findings indicate that hyperthermia augments the antitumor effects of curcumin in vitro, supporting the hypothesis that curcumin could be a more effective HIPEC agent than traditional drugs like mitomycin-C. Mutation-associated differences in response to treatments were observed, particularly in p53 mutant cells. While further studies are needed, these preliminary results suggest that curcumin in HIPEC could represent a novel therapeutic strategy for CRC patients with peritoneal metastases. This approach may offer improved outcomes with fewer side effects, particularly in genetically distinct CRC subtypes.
结直肠癌（CRC）的腹膜转移带来了重大的临床挑战，预后较差，通常对全身化疗无反应。细胞减灭术（CRS）联合腹腔内热灌注化疗（HIPEC）是针对部分患者的一种治疗方法。姜黄素是一种具有抗肿瘤特性的天然化合物，由于其与传统药物相比副作用较小，且通过直接注入腹腔有提高疗效的潜力，因此在HIPEC中的应用备受关注。
建立了一种体外热疗模型以模拟临床HIPEC条件。用姜黄素（25 μM）或丝裂霉素-C（1 μM）处理代表不同基因突变（p53、KRAS、BRAF）的三种结肠癌细胞系（SK-CO-1、COLO205、SNU-C1）1、2或3小时。处理后，将细胞在37°C（正常体温）或42°C（热疗）下孵育。在处理后24、48和72小时，使用膜联蛋白V/碘化丙啶、MTT法、台盼蓝排斥法和霍夫曼显微镜评估细胞活力和增殖情况。
热疗显著增强了姜黄素的抗肿瘤功效，所有细胞系在热疗条件下的细胞活力相较于正常体温均降低了两倍。在携带p53突变的SNU-C1细胞系中，与姜黄素不同，丝裂霉素-C未能显著影响细胞活力，这表明治疗反应存在突变特异性差异。
研究结果表明，热疗在体外增强了姜黄素的抗肿瘤作用，支持了姜黄素可能比丝裂霉素-C等传统药物更有效的HIPEC药物这一假设。观察到了治疗反应中与突变相关的差异，特别是在p53突变细胞中。虽然需要进一步研究，但这些初步结果表明，HIPEC中的姜黄素可能代表了一种针对腹膜转移CRC患者的新型治疗策略。这种方法可能在副作用较少的情况下提供更好的治疗效果，特别是在基因不同的CRC亚型中。
