Kahalalide F is a novel marine-derived antitumor agent known for inhibiting DNA synthesis. It exhibits cytotoxicity that is not correlated with the expression levels of the multidrug resistance gene MDR1 or the tyrosine kinase HER2/NEU, and is only slightly related to the expression of the anti-apoptotic protein BCL-2. Kahalalide F hinders the PI3K-Akt signaling pathway by depleting ErbB3. Its effects are rapidly activated with short pulse treatments. The compound primarily induces cell death through oncosis (cellular swelling) in tumor cells. Kahalalide F can be utilized in studies of prostate cancer, breast cancer, vulvar cancer, and non-small cell lung cancer.

Kahalalide F induces significant morphological changes in PC3 and SKBR-3 cells at 1 μM for 1 hour, causing severe cytoplasmic swelling and vacuolization without notable nuclear disruption. When applied at 0.1-10 μM for 24 hours, Kahalalide F exhibits dose-dependent inhibition of DNA synthesis in prostate cancer cells (PC3 (IC 50 = 0.07 μM), DU145 (IC 50 = 0.18 μM), LNCaP (IC 50 = 0.26 μM)) and breast cancer cells (SKBR-3 (IC 50 = 0.23 μM), MCF7 (IC 50 = 0.28 μM), BT474 (IC 50 = 0.26 μM)), indicating potent cytotoxicity. The compound is cytotoxic to PC3 cells whether exposed briefly (0.5-1 μM, 0-24 hours) or for extended periods, as 45-minute treatment is equally effective as 24-hour treatment, and 15-minute exposure achieves a half-maximal effect. Notably, Kahalalide F-induced cytotoxicity in PC3 cells (0.25-0.5 μM, 0-48 hours) does not rely on gene expression or caspase activity and neither causes cell cycle arrest nor DNA degradation. It causes a rapid, transient loss of mitochondrial membrane potential in PC3 cells at 0.25-0.5 μM for 0-24 hours, followed by high spontaneous fluorescence fragment formation and lysosomal integrity disruption after 24 hours. At 0.5 μM, Kahalalide F promotes endoplasmic reticulum microvesicle formation and disintegration while maintaining nuclear membrane integrity, leading to chromatin aggregation in irregular patterns without forming apoptotic bodies in PC3 cells. It also demonstrates antifungal activity against Candida albicans ATCC 90028 (IC 50 = 3.02 μM), Cryptococcus neoformans ATCC 90113 (IC 50 = 1.53 μM), and Aspergillus fumigatus ATCC 90906 (IC 50 = 3.21 μM). The in vitro cytotoxicity of Kahalalide F critically depends on ErbB3 protein expression. At 1 μM for 4 hours, it selectively downregulates ErbB3 expression in ErbB3-high expressing SKBR3 cells. Furthermore, Kahalalide F shows enhanced cytotoxicity in H460 cells at 1-2 μM for 4-72 hours, along with exogenous ErbB3 inhibition, increasing cell sensitivity and significantly lowering the IC 50 value from 4.7 μM to 3.1 μM.