Targeted paclitaxel‐octreotide conjugates inhibited the growth of paclitaxel‐resistant human non‐small cell lung cancer A549 cells in vitro. Issue 22 (6th October 2021)

• Record Type: Journal Article
• Authors: Liu, Yanguo; Xia, Handai; Wang, Yawei; Han, Wenfei; Qin, Jing; Gao, Wenjuan; Qu, Xun; Wang, Xiuwen
• Is Part Of: Thoracic cancer. Volume 12:Issue 22(2021)
• Page Start: 3053
• Page End: 3061
• Publication Date: 2021-10-06
• Subjects: cytotoxic analogs -- non‐small cell lung cancer -- paclitaxel resistance -- somatostatin receptors; Chest -- Cancer -- Periodicals; Chest -- Cancer -- Treatment -- Periodicals; Chest -- Surgery -- Periodicals; 616.99494005
• DOI: 10.1111/1759-7714.14182
• Languages: English
• ISSNs: 1759-7706

Abstract

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. Abstract : Targeted cytotoxic somatostatin analogs paclitaxel‐octreotide (PTX‐OCT) conjugates inhibited the growth and induced apoptosis of A549 cells in a SSTRs‐mediated manner, whereas they were less toxic to H157 (SSTRs‐negative) cells. PTX‐OCT and PTX‐2OCT significantly reverse paclitaxel resistance, with no or lower induction of MDR genes such as MDR‐1, MRP‐1, and BCRP than paclitaxel in vitro.