Spirulina pigment dismantles a key shield that blocks breast cancer drug response

Triple-negative breast cancer has long been the hardest breast cancer to drug. It lacks the estrogen and progesterone receptors and the HER2 protein that anchor most targeted therapies, leaving patients with blunt chemotherapy, immunotherapy combinations, and, for the minority carrying BRCA mutations, PARP inhibitors. Against that grim backdrop, a research team at Arak University of Medical Sciences in Iran reports an unexpectedly elegant trick: using a blue pigment harvested from spirulina algae to disassemble the molecular shield that tumors raise against a promising class of cell-death-inducing drugs. The study, published in Molecular Biology Reports, suggests that the natural compound C-phycocyanin can dismantle the specific survival machinery that makes triple-negative breast cancer cells stubbornly resistant to the BH3-mimetic ABT-737.

The drug at the center of the resistance story is ABT-737, a synthetic small molecule that belongs to the BH3-mimetic family. These compounds mimic a short protein segment, the Bcl-2 homology 3 domain, that pro-apoptotic proteins use to latch onto and neutralize their anti-apoptotic relatives. In healthy cells, the Bcl-2 protein family functions as a molecular checkpoint for apoptosis, the programmed self-destruction pathway that eliminates damaged or superfluous cells. The family contains pro-death effectors such as Bak and Bax, which punch holes in the outer mitochondrial membrane to trigger the apoptotic cascade, and anti-apoptotic guardians such as Bcl-2, Bcl-xL, and myeloid cell leukemia-1, or Mcl-1, which sequester those effectors and keep the checkpoint locked. BH3 mimetics pry that lock open. ABT-737 binds Bcl-2, Bcl-w, and Bcl-xL with high affinity, freeing Bak and Bax to initiate mitochondrial outer membrane permeabilization and release cytochrome c.

The fatal flaw of ABT-737, documented repeatedly since its 2005 debut in Nature, is what it cannot bind. Mcl-1 sits outside its reach, and cancer cells respond to Bcl-2 family pressure by leaning harder on Mcl-1 for survival. Prior work has shown that breast cancer cells frequently increase Mcl-1 expression when exposed to ABT-737, and that the drug performs dramatically better in cell lines where Mcl-1 is degraded or genetically silenced. In triple-negative breast cancer specifically, dependence on Mcl-1 has been traced to its canonical anti-apoptotic function, making the protein both a vulnerability and the principal escape route from Bcl-2-targeted therapy. Clinical efforts to develop selective Mcl-1 inhibitors have been beset by cardiac toxicity concerns, which has pushed researchers toward indirect strategies that lower Mcl-1 levels using existing or better-tolerated compounds.

Enter C-phycocyanin, the phycobiliprotein pigment that gives spirulina and other cyanobacteria their distinctive blue-green color. It is not an obscure molecule. Phycocyanin is consumed as a dietary supplement, has been investigated as a natural anti-inflammatory and antioxidant, and has accumulated a growing preclinical dossier of anti-cancer activity across breast, pancreatic, and gastrointestinal tumor models. Earlier studies in triple-negative breast cancer cells, including the aggressive MDA-MB-231 line, showed that the pigment suppresses proliferation and migration through the MAPK signaling pathway. What the new study adds is a precise mechanistic account of how C-phycocyanin interacts with the Bcl-2 family to convert ABT-737 from a partially effective drug into a synergistic killer.

The experimental system was deceptively simple. Shayesteh Khishavand and Hadi Karami cultured MDA-MB-468 cells, a well-characterized triple-negative breast cancer line that carries mutant p53 and an epidermal growth factor receptor amplification, and treated them with C-phycocyanin alone, ABT-737 alone, or the two drugs in combination. They then measured cell viability with MTT assays, proliferation with trypan blue exclusion, migratory capacity with wound healing assays, long-term reproductive survival with clonogenic assays, apoptosis with ELISA-based detection, and caspase-3 enzymatic activity. Expression of the key Bcl-2 family players was quantified at both the messenger RNA level by quantitative reverse transcription PCR and the protein level by Western blot. Drug interactions were formally assessed using the Combination Index method, a widely used framework in which values below one indicate synergy, values near one indicate additivity, and values above one indicate antagonism.

The numbers tell a striking story. On its own, C-phycocyanin inhibited half of the cells at a concentration of 5.62 micromolar, while ABT-737 required 32.47 micromolar to reach the same effect, reflecting the substantial intrinsic resistance of these cells to the BH3 mimetic. When the two agents were combined, the half-maximal inhibitory concentration of the drugs dropped to 3.71 micromolar, and the Combination Index fell below one, formally confirming a synergistic interaction. In practical terms, each drug needed less of itself to do more damage when partnered with the other, exactly the pharmacological profile that combination therapy seeks.

The molecular mechanism underlying that synergy resolved into a familiar pattern of compensatory resistance and its circumvention. When ABT-737 was applied alone, MDA-MB-468 cells raised Mcl-1 expression by roughly 40 percent, a textbook survival response to pressure on the Bcl-2 branch of the family. C-phycocyanin co-treatment effectively counteracted that response, holding Mcl-1 in check. Beyond blunting the adaptive Mcl-1 surge, the pigment also downregulated Bcl-2 itself while simultaneously increasing expression of Bak, the pro-apoptotic effector that ABT-737 liberates, and p53, the tumor suppressor that coordinates apoptotic responses to cellular stress. The net effect was to strip away the anti-apoptotic shielding while boosting the pro-apoptotic force, tilting the Bcl-2 family balance decisively toward mitochondrial breach.

Downstream readouts confirmed that the shift translated into genuine cell death and functional impairment. The combination produced significantly greater caspase-3 activation than either drug alone, indicating that the intrinsic apoptotic cascade had been engaged to completion. Apoptosis measured by ELISA rose in parallel. The partnership also constrained malignant behavior beyond the dish-level kill: cells treated with both drugs migrated far less effectively in wound healing assays and formed markedly fewer colonies, suggesting that the combination impairs both dissemination potential and the self-renewal capacity required for tumor propagation, not merely acute viability.

The authors are appropriately measured about the scope of their findings. The work rests on a single cell line, and MDA-MB-468, with its mutant p53 and EGFR amplification, represents only one molecular identity within the heterogeneous universe of triple-negative breast cancer. The study itself notes that further validation in additional triple-negative cell lines is warranted, and the jump from two-dimensional cultures to animal models and, ultimately, patients remains long and uncertain. C-phycocyanin’s pharmacokinetics, bioavailability, and safety profile at efficacious doses in humans are not established by this work, and ABT-737 itself was succeeded clinically by orally bioavailable derivatives such as navitoclax and venetoclax, which carry their own resistance and toxicity profiles.

Even with those caveats, the study lands at a moment of genuine momentum for apoptosis-targeted cancer therapy. The conceptual advance is that a well-tolerated natural product, rather than a bespoke synthetic Mcl-1 inhibitor, can suppress the compensatory pathway that limits BH3-mimetic efficacy, opening a lower-toxicity route to rational combination design. It also reinforces a principle that has emerged across multiple tumor types: the predictive value of Mcl-1 levels for BH3-mimetic response, and the therapeutic value of manipulating those levels directly. Whether C-phycocyanin can make that leap from pigment to pharmaceutical partner will depend on the validation studies that must now follow, but for a cancer with so few molecular handles, the identification of a new one, plucked from a common blue-green alga, is a result worth watching closely.

Subject of Research: Overcoming ABT-737 resistance in triple-negative breast cancer through C-phycocyanin-mediated Mcl-1 downregulation

Article Title: Overcoming ABT-737 resistance in triple-negative breast cancer: C-phycocyanin-mediated myeloid cell leukemia-1 downregulation enhances apoptotic sensitivity

Article References: Khishavand, S., & Karami, H. (2026). Overcoming ABT-737 resistance in triple-negative breast cancer: C-phycocyanin-mediated myeloid cell leukemia-1 downregulation enhances apoptotic sensitivity. Molecular Biology Reports, 53(1), Article 1614. https://doi.org/10.1007/s11033-026-12824-5

Image Credits: AI Generated

DOI: 10.1007/s11033-026-12824-5

Keywords: triple-negative breast cancer, ABT-737, C-phycocyanin, Mcl-1, BH3 mimetics, apoptosis, drug synergy, Bcl-2 family, combination therapy, MDA-MB-468, caspase-3, natural products