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We queried whether cancer treatment by combinations of paclitaxel and butyrate – free or formulated in drug delivery systems – can improve therapeutic responses compared to each drug alone. Combination treatments were conducted with HT-29 and HeLa cells, as representatives of differentiation-induced and cell-death-induced cancer lines, respectively. Pre-treatment of the HT-29 cells with butyrate (at doses inducing differentiation), followed by butyrate + paclitaxel generated changes in cell cycle profile, increased the level of dead cells beyond that of each drug alone, and allowed reduction in paclitaxel doses. A similar combination treatment of HeLa cells was detrimental, indicating that whether the combination is beneficial or not is cancer-type specific. We hypothesize that while butyrate-treated HT-29 cells became sensitive to paclitaxel-induced Fas-mediated apoptosis, butyrate-adapted HeLa cells became apoptosis-resistant. We next tested the same drug combination on HT-29 cells, but each drug in a specific tumor-targeted carrier. The combination of drug carriers outperformed an equidose combination of the free drugs, showing potential to achieve high therapeutic responses (even in drug-resistant cells) at significantly lower and detergent-free paclitaxel doses, which should allow for reduction in adverse effects and risks of toxicity.