The proton pump inhibitor lansoprazole (LPZ) inhibits the growth of several cancer cell lines, including A549 and CAL 27. We previously reported that macrolide antibiotics such as azithromycin (AZM) and clarithromycin (CAM) potently inhibit autophagic flux and that combining AZM or CAM with the epidermal growth factor receptor inhibitors enhanced their antitumor effect against various cancer cells. In the present study, we conducted the combination treatment with LPZ and macrolide antibiotics against A549 and CAL 27 cells and evaluated cytotoxicity and morphological changes using cell proliferation and viability assays, flow cytometric analysis, immunoblotting, and morphological assessment. Combination therapy with LPZ and AZM greatly enhanced LPZ-induced cell death, whereas treatment with AZM alone exhibited negligible cytotoxicity. The observed cytotoxic effect was not mediated through apoptosis or necroptosis. Transmission electron microscopy of A549 cells treated with the LPZ + AZM combination revealed morphological changes associated with necrosis and accumulated autolysosomes with undigested contents. Furthermore, the A549 cell line with ATG5 knockout exhibited complete inhibition of autophagosome formation, which did not affect LPZ + AZM treatment-induced cytotoxicity, thus excluding the involvement of autophagy-dependent cell death in LPZ + AZM treatment-induced cell death. A549 cells treated with LPZ + AZM combination therapy retained the endosomal Alexa-dextran for extended duration as compared to untreated control cells, thus indicating impairment of lysosomal digestion. Notably, lysosomal galectin-3 puncta expression induced due to lysosomal membrane permeabilization was increased in cells treated with LPZ + AZM combination as compared to the treatment by either agent alone. Collectively, the present results revealed AZM-induced autolysosome accumulation, potentiated LPZ-mediated necrosis, and lysosomal membrane permeabilization, thus suggesting the potential clinical application of LPZ + AZM combination therapy for cancer treatment.
KeywordsEctopic thyroid cancer · Occult thyroid cancer · Papillary thyroid carcinoma · Symptomatic papillary thyroid microcarcinoma Abstract Herein, we report a case of an occult thyroid cancer that was not detected as a primary tumor on preoperative ultrasonography or postoperative pathological examination, although a diagnosis of papillary thyroid carcinoma metastasis was made owing to the presence of a mass in the right upper neck. Needle biopsy of the mass in the right upper neck revealed positive results for thyroglobulin and TTF-1 on immunostaining, and a papillary thyroid carcinoma was observed with papillary and follicular patterns. We suspected papillary thyroid carcinoma (T0N1bM0) or ectopic papillary thyroid carcinoma. Accordingly, we performed total thyroidectomy, central lymph node dissection, right lateral neck dissection, and resection of the superficial lobe of the right parotid. A postoperative pathological examination of 5-mm slices of the specimen revealed no primary tumor in the thyroid. However, a hyalinized image of the thyroid indicated that a micropapillary thyroid carcinoma might have spontaneously disappeared. As there was no normal thyroid tissue in the metastasis to the superior internal jugular lymph node, the tumor was unlikely to be an ectopic papillary thyroid carcinoma. Therefore, we made a diagnosis of a papillary thyroid carcinoma (pT0N1bM0). After surgery, we determined that the tumor belonged to a high-risk group of papillary thyroid carcinomas and a poor-prognosis group of symptomatic papillary thyroid microcarcinomas; accordingly, ablation was performed with 30 mCi iodine-131. There was no recurrence or metastasis 24 months after the first surgery.
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