海报库PosterKeep
PO.ET08.03 · 实验与分子治疗

新一代肿瘤治疗电场技术与肉桂醛/肉桂油对三阴性乳腺癌细胞凋亡、细胞周期阻滞及生长抑制的协同作用

Synergistic effects of next-generation Tumor-Treating Fields technology and cinnamaldehyde/cinnamon oil on apoptosis, cell cycle arrest and growth suppression in triple-negative breast cancer cells

编号 7198 展板 17 时间 4/22 09:00–12:00 区域 Section 17 主讲 Saqib Peracha
分会场 Targeted Radiopharmaceuticals and Combination Strategies in Cancer Therapy
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作者与单位 Authors & Affiliations

Saqib N. Peracha1, Joseph M. Rohde2, Margaux A. Santos2, Emma C. Higgins2, Lexa M. Campbell2, Wageesha T. Mallehevidana3, Juliana R. Seide2, Aidan Hollister2, Therese M. Annulis2, Abdu Mohammed1, Kiran Khurshid1, Noor U. Huda1, Aaron P. Provenzano4, Jason R. Henderson5, Daniel Kuebler2, Joseph A. Pathakamuri2, John J. O'Connell6

1Trinity Health System, Steubenville, OH,2Department of Biology, Franciscan University of Steubenville, Steubenville, OH,3Department of Bioengineering, Swanson School of Engineering, University of Pittsburgh, Pittsburgh, PA,4Hillman Cancer Center, University of Pittsburgh Medical Center, Pittsburgh, PA,5Quiverent, LLC., Greenville, SC,6University of South Carolina School of Medicine Greenville, Greenville, SC; Department of Medicine, Prisma Health Cancer Institute, Greenville, SC

摘要 Abstract

中文摘要
背景:三阴性乳腺癌(TNBC)是乳腺癌中最具侵袭性的亚型之一,占乳腺癌的10-20%。肿瘤治疗电场(TTF)可破坏有丝分裂纺锤体的形成并诱导TNBC细胞凋亡。肉桂醛(CA)是肉桂的活性成分,可抑制TNBC增殖并促进凋亡。本研究评估CA或肉桂油(CO)是否与TTF协同作用,以增强对TNBC细胞的生长抑制、凋亡和细胞周期阻滞。 方法:将MDA-MB-231 TNBC细胞以75,000个细胞/mL接种,并用CA(150 μM)、CO(1:300稀释)或载体对照处理。以调频TTF(FM-TTFields)在150 kHz(采用8.3 mHz三角波进行±10 kHz调制)、1.2 V RMS/cm下连续施加72小时。通过CyQUANT法和Celigo成像评估细胞增殖;通过Annexin V/PI流式细胞术分析凋亡和细胞周期分布。使用Bliss独立模型和最高单药(HSA)模型对协同作用进行量化。 结果: 细胞死亡协同作用:联合处理TTF+CA(96.7%)和TTF+CO(96.3%)所致的细胞死亡超过单药CA(93.6%)、CO(86.1%)和TTF(40.0%)。通过HSA和Bliss模型进行的协同分析证实了协同作用,TTF+CO(HSA Δ = +10.3 ± 2.5分(pts),p = 0.02;Bliss Δ = +4.7 ± 1.7分,p = 0.042)强于TTF+CA(HSA Δ = +3.2 ± 1.4分,p = 0.06;Bliss Δ = +0.9 ± 1.0分,p = 0.27)。TTF与CA或CO联合产生协同获益,其中TTF+CO效果最大。 凋亡协同作用(Annexin V/PI):TTF+CO(49.9%)和TTF+CA(65.5%)大幅超过CA(20.6%)、CO(13.9%)和TTF(1.4%)。联合使凋亡增加约36倍(TTF+CO)和约48倍(TTF+CD)。TTF+CA的协同作用最高(HSA Δ = +44.3分;Bliss Δ = +43.2分),高于TTF+CO(HSA Δ = +35.1分;Bliss Δ = +33.9分)。TTF与CA或CO联合可显著增强凋亡,其中TTF+CA最为有效。 细胞周期调控:相对于DMSO,CA和CO富集了S期(Δ%:CO +10分;CA +8分)。TTF诱导了强烈的G2/M期蓄积(+18分)。TTF与CO联合进一步增加了G2/M期(+12分),而S期变化极小(+1分),而CA+TTF仅产生较小的G2/M期移位(+2分)。这些模式提示机制上的互补性:CA和CO主要将细胞阻滞于S期,而TTF诱导有丝分裂阻滞(M期)。 结论:FM-TTFields与肉桂油或肉桂醛联合,通过互补机制——S期阻滞和有丝分裂破坏——增强TNBC细胞死亡和凋亡,使FM-TTFields与肉桂油或肉桂醛联合产生显著协同作用。这些发现支持一种治疗TNBC的新型联合策略。未来研究应在体内验证这些结果并探索临床转化。
查看英文原文 English abstract
Background: Triple-negative breast cancer (TNBC), one of the most aggressive subtypes of breast cancer, accounts for 10-20% of breast cancers. Tumor-Treating Fields (TTF), disrupt mitotic spindle formation and induce apoptosis in TNBC cells. Cinnamaldehyde (CA), the active component of cinnamon, inhibits TNBC proliferation and promotes apoptosis. This study evaluated whether CA or cinnamon oil (CO) acts in synergy with TTF to enhance growth suppression, apoptosis, and cell-cycle arrest in TNBC cells. Methods: MDA-MB-231 TNBC cells were seeded at 75,000 cells/mL and treated with CA (150 µM), CO (1:300 dilution), or vehicle controls. Frequency-modulated TTF (FM-TTFields) were applied continuously for 72 hours at 150 kHz (±10 kHz modulation using an 8.3 mHz triangle wave), 1.2 V RMS /cm. Cell proliferation was assessed by CyQUANT assay and Celigo imaging; apoptosis and cell-cycle distribution were analyzed by Annexin V/PI flow cytometry. Synergy was quantified using Bliss independence and Highest Single Agent (HSA) models. Results: Cell death synergy: Cell death from combined treatments TTF+CA (96.7%) and TTF+CO (96.3%) exceeded single agents CA (93.6%), CO (86.1%), and TTF (40.0%). Synergy analysis by HSA and Bliss models confirmed synergy, stronger for TTF+CO (HSA Δ = +10.3 ± 2.5 points (pts), p = 0.02; Bliss Δ = +4.7 ± 1.7 pts, p = 0.042) than TTF+CA (HSA Δ = +3.2 ± 1.4 pts, p = 0.06; Bliss Δ = +0.9 ± 1.0 pt, p = 0.27). Combining TTF with CA or CO yields synergistic benefits, with TTF+CO showing the greatest effect. Apoptosis synergy (Annexin V/PI): TTF+CO (49.9%) and TTF+CA (65.5%) greatly surpassed CA (20.6%), CO (13.9%), and TTF (1.4%). Combinations increased apoptosis ~36-fold (TTF+CO) and ~48-fold (TTF+CD). Synergy was highest for TTF+CA (HSA Δ = +44.3 pts; Bliss Δ = +43.2 pts) versus TTF+CO (HSA Δ = +35.1 pts; Bliss Δ = +33.9 pts). Combining TTF with CA or CO substantially enhances apoptosis, with TTF+CA most effective. Cell-cycle modulation: CA and CO enriched the S phase relative to DMSO (Δ%: CO +10 pts; CA +8 pts). TTF induced strong G2/M accumulation (+18 pts). Combining TTF with CO further increased G2/M (+12 pts) with minimal S-phase change (+1 pt), while CA+TTF produced only a small G2/M shift (+2 pts). These patterns suggest mechanistic complementarity: CA and CO primarily arrest cells in the S phase, whereas TTF induce mitotic arrest (M phase). Conclusions: Combining FM-TTFields with cinnamon oil or cinnamaldehyde enhances TNBC cell death and apoptosis through complementary mechanisms-S-phase arrest and mitotic disruption-resulting in significant synergy for FM-TTFields combined with cinnamon oil or cinnamaldehyde. These findings support a novel, combinatorial strategy for treating TNBC. Future studies should validate these results in vivo and explore clinical translation.
利益披露 Disclosure
S. N. Peracha, None.. J. M. Rohde, None.. M. A. Santos, None.. E. C. Higgins, None.. L. M. Campbell, None.. W. T. Mallehevidana, None.. J. R. Seide, None.. A. Hollister, None.. T. M. Annulis, None.. A. Mohammed, None.. K. Khurshid, None.. N. U. Huda, None.. A. P. Provenzano, None. J. R. Henderson, Pensievision Independent Contractor, Other, Consultant. D. Kuebler, None.. J. A. Pathakamuri, None.. J. J. O'Connell, None.

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