Rational combination of natural and synthetic derivatives to treat lung cancer has advantages of both efficacy and safety. Herein, the combination of indirubin‐3‐monoxime (I3M), a chemical derived from Chinese herbal medicine and FXY‐1, a synthetic arylidene derivative, was tested for combined activity in lung cancer cells. A dose‐dependent synergistic reduction in cell viability was recorded with the combinations in A549 and NCI‐H460 cells. Combination treatments of I3M and FXY‐1 showed antimetastatic effects in both cells. Cell cycle analysis revealed G1 growth phase reduction with subsequent accumulation of sub G0 contents. Annexin V assay revealed higher apoptotic cells with combinations compared to individual treatments. I3M + FXY‐1 combination significantly decreased the antiapoptotic Bcl‐2 protein and increased pro‐apoptotic Bax protein levels. These results demonstrate efficacy of I3M + FXY‐1 in lung cancer cells and suggest further preclinical research in animal models to develop it into a new form combination chemotherapeutic against lung cancer. Practical applications Current investigation will open new options in rational combinations of natural and synthetic compounds to treat cancer. The observed efficacy and safety of the combinations will add to the advantage of higher therapeutic window in formulating treatment regimens. The antimetastatic effects by the combinations provides promising efficacy in controlling the lung cancer progression. A detailed in vivo investigation is recommended to transform the combinations to novel chemotherapeutic options against lung cancer.

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