Targeted paclitaxel-octreotide conjugates inhibited the growth of paclitaxel-resistant human non-small cell lung cancer A549 cells in vitro.

The application of chemotherapy in non-small cell lung cancer (NSCLC) is limited by the toxicity to normal cells and the development of multi-drug resistance. Targeted chemotherapy using cytotoxic analogs against specific receptors on cancer cells could be a less toxic and more efficacious approach. We identified that the expressions of somatostatin receptor (SSTR) 2 and 5 in tumor tissues from NSCLC patients were higher than those in the adjacent normal tissues by immunohistochemistry, and therefore, cytotoxic somatostatin analogues might be applied for SSTRs-mediated targeted therapy against NSCLC. Two cytotoxic analogs, paclitaxel-octreotide (PTX-OCT) and 2paclitaxel-octreotide (2PTX-OCT), were synthesized by linking one or two molecules of paclitaxel to one molecule of somatostatin analog octreotide. PTX-OCT and 2PTX-OCT significantly inhibited the growth and induced apoptosis of SSTR2- and SSTR5-positive A549 cells, compared with the control (p < 0.01), and had less inhibitory effect on SSTR2- and SSTR5-negative H157 cells than paclitaxel (p < 0.01). Moreover, compared with paclitaxel, PTX-OCT conjugates induced lower expression of MDR-1 gene both in vitro and in vivo. Three A549 paclitaxel-resistant cell lines were established through different approaches, and the paclitaxel-resistant cell showed higher sensitivity to PTX-OCT conjugates than to paclitaxel, which might be because of the differential MDR-related gene expressions and cell-cycle distribution in paclitaxel-resistant A549 cells. Our results suggested that PTX-OCT conjugates could be potentially used for SSTRs-mediated targeted therapy for NSCLC, especially for those with paclitaxel resistance and induced less multidrug resistance.