Aloe vera extract disrupts mitochondrial bioenergetics and suppresses HeLa cervical cancer cell proliferation: Transcriptomic and metabolic insights into cisplatin co-treatment.
Cervical cancer remains a leading cause of cancer related mortality in women worldwide. Cisplatin (CP) is a cornerstone chemotherapeutic agent; however, its clinical utility is constrained by dose-limiting toxicity and the emergence of drug resistance, necessitating novel combinatorial strategies. This study investigated the therapeutic potential of combining CP with Aloe vera extract (AVE) against HeLa cervical cancer cells and the normal human skin fibroblast cell line CCD-1072Sk. Cytotoxicity assays performed using the xCELLigence Real-Time Cell Analysis (RTCA) system determined IC50 values of 18.45 µM for CP and 18.88 µg/mL for AVE in HeLa cells, compared with 53.31 µM and 19.09 µg/mL, respectively, in CCD-1072Sk cells. The CP + AVE combination exhibited markedly enhanced antiproliferative activity in HeLa cells compared with CP alone, while CCD-1072Sk cells exhibited continued but decelerated proliferation, suggesting a differential cellular response. Seahorse metabolic analysis revealed that AVE, both alone and in combination with CP, markedly increased mitochondrial oxygen consumption rate (OCR) and ATP-linked respiration in HeLa cells, indicating induction of sustained bioenergetic stress beyond the cells' adaptive capacity. Transcriptomic profiling of HeLa cells identified 453 differentially expressed genes (DEGs) upon combination treatment, with significant downregulation of oxidative phosphorylation (OXPHOS) components, mitochondrial electron transport chain subunits, and the fatty acid metabolism gene CPT1B, collectively indicating a severe disruption of cellular energy metabolism. DepMap database analysis confirmed that downregulated targets including CPT1B and CHN2 are functionally important for HeLa cell survival. Collectively, these data suggest that AVE drives HeLa cells into a hypermetabolic state that overloads mitochondrial capacity; in combination with CP, this converging bioenergetic stress produces enhanced cytotoxicity descriptively consistent with an additive interaction (a term used here in its dose-response sense, as no formal combination-index or Bliss/Loewe synergy analysis was performed) at the IC50 doses employed. This study highlights the potential of AVE as a metabolically active combinatorial agent capable of potentiating CP efficacy by targeting cancer cell energy metabolism, and provides a mechanistic basis for further investigation.