The research, led by Thoria Donia and Mohamed Hessien along with colleagues at Tanta University and collaborating Egyptian institutes, focused on two cell lines that loom large in cancer biology. HepG2 cells, derived from a human hepatocellular carcinoma, represent the most common form of liver cancer and a leading cause of cancer death worldwide. MDA-MB-231 cells, meanwhile, are a notoriously aggressive model of triple-negative breast cancer, the subtype that resists hormone therapy and targeted drugs alike. The team measured how much chlorpromazine was needed to kill half of the cells in each culture, a standard benchmark known as the IC50. When mdivi-1 was added alongside the antipsychotic, that lethal dose dropped in both cell lines, with the liver cancer cells proving noticeably more responsive than their breast cancer counterparts.

That synergy is not accidental, and the study’s technical work explains why it happens. Mdivi-1 was originally identified in 2008 as a small molecule that blocks dynamin-related protein 1, or Drp1, the molecular engine that pinches mitochondria in two during cell division of these organelles. Cancer cells are famously dependent on finely tuned mitochondrial dynamics, the constant cycling of fusion and fission that keeps their powerhouses distributed, their metabolism flexible, and their survival machinery primed. By jamming the fission machinery, mdivi-1 throws that balance into disarray. Chlorpromazine, for its part, has long been known to disrupt clathrin-mediated endocytosis, the cellular trafficking route that tumors exploit for growth signaling, and earlier studies have shown it can trigger cell cycle arrest and autophagy in cancers ranging from glioblastoma to colorectal tumors.

To probe what the combination was actually doing inside the cells, the researchers deployed a battery of assays that read out the hallmarks of dying and migrating cancer cells. Annexin V and propidium iodide staining, which flags the flipping of membrane phospholipids that marks early apoptosis, revealed a surge in programmed cell death under the dual treatment. Acridine orange and ethidium bromide, together with DAPI staining, exposed the nuclear signature of apoptosis: chromatin condensing into dense, fragmented clumps as the genome was dismantled. The combination also compromised cell membrane integrity, a sign that the cells were losing the structural coherence needed to survive. In clonogenic assays, which test whether single cells can found new colonies over days to weeks, the treated cultures produced far fewer colonies, indicating that the damage was not merely a transient shock but a lasting blow to reproductive capacity.

Migration, the behavior that lets tumors seed metastases throughout the body, was similarly throttled. In wound-healing assays, where a scratch is made across a confluent cell layer and the researchers watch how quickly cells crawl in to close the gap, the combination-treated cells moved sluggishly compared with controls. Behind that physical slowdown lay a molecular shift in epithelial-mesenchymal transition, the developmental program that cancer cells hijack to become mobile and invasive. The team found that the dual treatment downregulated the expression of vimentin and DDR2, two mesenchymal markers that signal a cell’s conversion into the migratory, invasive state. Suppressing this program is a major therapeutic goal in oncology, because mesenchymal tumor cells are typically the ones that break away, circulate, and establish deadly secondary tumors.

The mitochondrial story proved to be the most intricate thread of the study. On its own, mdivi-1 upregulated the expression of the fusion genes MFN1, MFN2, and OPA1, which encode the proteins that merge mitochondria and preserve their functional network. But when chlorpromazine entered the picture, the picture changed: the combined treatment dysregulated both the fusion and the fission gene sets, throwing the entire dynamical system out of balance. This matters because tumor cells rely on a specific rhythm of mitochondrial remodeling to support their abnormal metabolism and to evade apoptosis. Disrupting both sides of the fusion-fission equilibrium at once appears to deprive the cells of the flexibility they need to adapt, compounding the stress imposed by chlorpromazine itself.

Oxidative stress emerged as the engine that converts that mitochondrial chaos into cell death. Using 2′,7′-dichlorodihydrofluorescein diacetate staining, a fluorescent probe that lights up in the presence of reactive oxygen species, the researchers documented an overproduction of cellular ROS in the treated cells. At the same time, the cells’ antioxidant capacity was depleted, and the expression of Nrf2, the master transcription factor that orchestrates the cellular antioxidant response, was downregulated. Nrf2 is a double-edged sword in cancer: many tumors crank it up to neutralize the oxidative byproducts of their runaway metabolism and to resist chemotherapy. By suppressing Nrf2 while simultaneously flooding the cells with ROS, the drug combination stripped cancer cells of both the insult and the defense, leaving them with no route back to equilibrium except apoptosis.

The broader context makes the result more than a laboratory curiosity. Chlorpromazine belongs to a growing list of central nervous system drugs being reexamined as anticancer agents, a strategy that appeals to researchers because these compounds have decades of clinical safety data, known pharmacokinetics, and low manufacturing costs. Recent studies have shown phenothiazines can suppress proliferation in leukemic cells while sparing normal lymphocytes, overcome temozolomide resistance in glioblastoma by interfering with DNA repair pathways, and suppress the YAP signaling axis that drives stemness and drug resistance in breast cancer. Chlorpromazine has also been shown to induce G2/M cell cycle arrest in colorectal and oral cancer cells. Meanwhile, mdivi-1 has independently attracted attention for sensitizing cancer cells to cisplatin and paclitaxel and for suppressing oxidative metabolism in tumors, making the two drugs natural partners in a combination strategy.

Cautions remain before any of this reaches patients. The work was conducted entirely in cell culture, and the gap between a dish of HepG2 cells and a living tumor is wide, encompassing drug delivery, metabolism, immune interactions, and toxicity that no in vitro system can fully model. Chlorpromazine itself carries known liabilities, including hepatotoxicity under inflammatory conditions and extrapyramidal neurological side effects at antipsychotic doses, and the study’s authors and prior literature alike note that safety profiling would be essential. The researchers also point to ongoing efforts to design chlorpromazine derivatives that retain anticancer activity while shedding the neurological side effects, an approach that could yield cleaner candidates. Still, the convergence of a repurposed psychiatric drug with a mitochondrial dynamics inhibitor offers a mechanistically coherent blueprint: attack the trafficking, the power grid, and the antioxidant shield of a tumor cell all at once.

What makes the study resonate beyond its immediate findings is the way it reframes an old drug through a modern lens. Mitochondrial dynamics has moved from a niche organelle-biology topic to a recognized axis of cancer vulnerability, and the Tanta team’s data show that a fission inhibitor can convert a moderately cytotoxic antipsychotic into a substantially more potent anticancer combination. The work was supported by Egypt’s Academy of Scientific Research and Technology and the Science and Technology Development Fund, and the authors report no competing interests. For now, the combination lives in the realm of preclinical promise, but it strengthens the case for clinical exploration of phenothiazine-based regimens, particularly for liver and triple-negative breast cancers where treatment options remain painfully limited. If subsequent animal and human studies bear out the synergy, a drug that has treated the mind since the Eisenhower era may yet earn a second career treating the body.

Subject of Research: Repurposing chlorpromazine combined with the mitochondrial fission inhibitor mdivi-1 as an anticancer strategy in liver and breast cancer cell lines

Article Title: Mdivi-1 augments chlorpromazine’s anticancer effect via modulation of mitochondrial dynamics, hallmarks of cancer-related cellular behavior, and oxidative stress

Article References: Donia, T., Ismail, D. F., Alkafaas, S. S., Adly, E., Tabll, A. A., & Hessien, M. (2026). Mdivi-1 augments chlorpromazine’s anticancer effect via modulation of mitochondrial dynamics, hallmarks of cancer-related cellular behavior, and oxidative stress. Medical Oncology, 43(11), Article 325. https://doi.org/10.1007/s12032-026-03364-w

Image Credits: AI Generated

DOI: 10.1007/s12032-026-03364-w

Keywords: chlorpromazine, mdivi-1, mitochondrial dynamics, drug repurposing, HepG2, MDA-MB-231, apoptosis, oxidative stress, Nrf2, epithelial-mesenchymal transition, mitochondrial fission, Medical Oncology