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04.12.2018 | Original Article | Ausgabe 3/2019

Cancer Chemotherapy and Pharmacology 3/2019

Self-targeted knockdown of CD44 improves cisplatin sensitivity of chemoresistant non-small cell lung cancer cells

Zeitschrift:
Cancer Chemotherapy and Pharmacology > Ausgabe 3/2019
Autoren:
Yu Hua Quan, Ji-Young Lim, Byeong Hyeon Choi, Yeonho Choi, Young Ho Choi, Ji-Ho Park, Hyun Koo Kim
Wichtige Hinweise

Electronic supplementary material

The online version of this article (https://​doi.​org/​10.​1007/​s00280-018-3737-y) contains supplementary material, which is available to authorized users.

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Abstract

Background

Chemoresistance remains a major challenge for effective chemotherapy of non-small-cell lung carcinoma (NSCLC). CD44 expression is related to the susceptibility of various cancer cell types to anticancer drugs. Here, we systematically investigated the CD44-dependent chemoresistance of NSCLC cells and developed a liposomal siRNA delivery system to overcome this chemoresistance by the self-targeted downregulation of CD44.

Methods

We confirmed the relationship between the expression of CD44 and the chemosensitivity of NSCLC cells using flow cytometry and MTT assay. We then generated and characterized cisplatin-resistant cell lines and compared the expression of CD44 in resistant cells to that in parental cells using western blotting. To evaluate whether the chemosensitivity of resistant cells depends on CD44 expression, we performed CD44 knockdown using CD44 siRNA and detected the chemosensitivity of these cells. Additionally, we prepared hyaluronic acid (HA)-coated liposomes as a targeted delivery system to selectively deliver CD44-specific siRNA to chemoresistant NSCLC cells and observed whether the chemosensitivity of these cells was improved.

Results

We found that CD44 expression is inversely proportional to the degree of cellular response to cisplatin chemotherapy and that CD44 is overexpressed in chemoresistant NSCLC cells. By performing CD44 knockdown using siRNA, we reconfirmed that the chemosensitivity of resistant cells depends on CD44 expression. We also observed that HA-liposome-mediated siRNA delivery prior to cisplatin chemotherapy significantly reduced CD44 expression and enhanced cisplatin sensitivity in chemoresistant NSCLC cells.

Conclusions

These results suggest that self-targeted downregulation of chemoresistance-associated cell surface proteins during chemotherapy is an effective therapeutic strategy for overcoming the chemoresistance of NSCLC cells.

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Zusatzmaterial
Supplementary material 1 (DOCX 13 KB)
280_2018_3737_MOESM1_ESM.docx
Supplementary Fig. 1. Preparation of HA-liposomes for CD44-targeted siRNA delivery. (A) The hydrodynamic sizes of 5- and 700-kDa HA-liposomes were approximately 144.2 and 156.4 nm, respectively. (B) The 700-kDa HA-liposomes showed notably higher targeting towards CD44-overexpressing H1299 and H1793 cells than H522 and H2087 cells which expressed low levels of CD44. (C) The 1:1 ratio of siRNA to protamine is optimized size for encapsulation of HA-liposomes. (D) Scheme of procedure to prepare siRNA-loaded HA-liposomes. (DOCX 178 KB)
280_2018_3737_MOESM2_ESM.docx
Supplementary material 3 (DOCX 22 KB)
280_2018_3737_MOESM3_ESM.docx
Literatur
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