The search for novel drug candidates is a priority goal for cancer therapy. Natural products isolated from plants are often used as valuable leads for the synthesis of analogs with simpler structure. Two synthetic α-methylene-δ-lactones with chroman-2-one skeleton, designated DL-3 and DL-5, exhibiting strong cytotoxic activity against several cancer cell lines, have been tested alone and in combination with well-known anticancer drugs, 5-fluorouracil, oxaliplatin, and taxol, in breast cancer MCF-7 cells. Parthenolide, a plant-derived α-methylene-γ-lactone, was used as a positive control. The effects on cell proliferation, DNA damage, and apoptosis induction were evaluated. Neither of the tested compounds significantly enhanced the effects produced by taxol, but a strong synergistic effect was observed with 5-fluorouracil and oxaliplatin. Only small differences between the actions of both α-methylene-δ-lactones were found. The synergistic effects produced by these compounds in MCF-7 cells were stronger as compared with parthenolide. Our findings show that simple and easy-to-obtain synthetic compounds with α-methylene-δ-lactone motif can potentiate the efficiency of anticancer drugs.