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

Abstract

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.

Small Molecule–Drug Conjugates Emerge as a New Promising Approach for Cancer Treatment

“…Knowing that octreotide has two amino groups in its structure and both can participate in compound coupling, Liu et al synthesized two cytotoxic conjugates paclitaxel-octreotide (PTX-OCT) and 2-paclitaxel-octreotide (2PTX-OCT)] to target octreotide by coupling one or two paclitaxel molecules to octreotide. Compared with paclitaxel, PTX-OCT and 2PTX-OCT significantly inhibited the growth and induced apoptosis of SSTR2 and SSTR5 positive A549 cells ( p < 0.01), and had lower inhibitory effects on SSTR2 and SSTR5 negative H157 cells as compared with paclitaxel ( p < 0.01) . In addition, compared with paclitaxel, PTX-OCT conjugate decreased the expression of MDR-1 gene both in vitro and in vivo, which should be able to effectively overcome the problem of drug resistance, suggesting that octreotide has potential advantages as a ligand for targeted drug delivery.…”

“…Compared with paclitaxel, PTX-OCT and 2PTX-OCT significantly inhibited the growth and induced apoptosis of SSTR2 and SSTR5 positive A549 cells (p < 0.01), and had lower inhibitory effects on SSTR2 and SSTR5 negative H157 cells as compared with paclitaxel (p < 0.01). 39 In addition, compared with paclitaxel, PTX-OCT conjugate decreased the expression of MDR-1 gene both in vitro and in vivo, which should be able to effectively overcome the problem of drug resistance, suggesting that octreotide has potential advantages as a ligand for targeted drug delivery.…”