Abstract
Accumulated evidence has shown that the photosensitizer Verteporfin (VP) may be an ideal agent for various cancer types. However, the effect and mechanism of VP on human cervical carcinoma remain rudimentary. The aim of this study was to investigate the effect of VP on human cervical carcinoma cells (HeLa and SiHa cells) and to elucidate the possible mechanism. CCK-8, wound healing assay, flow cytometry analysis, western blotting, TUNEL staining were performed to evaluate the effects of VP on HeLa and SiHa cells in vitro as well as in vivo on a xenograft model. In addition, the role of endoplasmic reticulum (ER) stress in VP-induced apoptosis was investigated using RT-qPCR and western blotting. The results showed that the viability of HeLa and SiHa cells was suppressed by VP in dose- and time-dependent manners. Compared with the control group, apoptosis rates were higher with stronger TUNEL fluorescence signals in the experimental group, which substantiated that VP induced apoptosis at both 2D and 3D cell levels. Besides, VP can squelch the growth of tumors in both sizes and weights on the xenograft models without impairing ovarian reserve. Mechanism studies demonstrated that VP activated ER stress by upregulating the expression of GRP78, CHOP, and Caspase-12, and VP-induced apoptosis can be alleviated when ER stress pathway was inhibited. Our results provided a foundation for repurposing VP as a promising agent for cervical cancer patients without obvious reproductive toxicity by targeting ER stress pathway, and more researches are required to support its application in clinical practice.
Highlights
An annual mortality of 266,000 with 528,000 incidence cases worldwide made cervical cancer the most common carcinoma in female reproductive system [1]
The results showed that the intensity of TUNEL fluorescence signals was higher in the experimental group in both HeLa and SiHa cells (Figure 2C), which indicated that cell apoptosis can be induced by VP at 3D cell level
The results showed that compared with the control group, the proportion of wound closures in the VP group was significantly decreased in both 24 h and 48 h (Figures 1C,D), which indicated that VP could significantly inhibit the migration of human cervical carcinoma cells
Summary
An annual mortality of 266,000 with 528,000 incidence cases worldwide made cervical cancer the most common carcinoma in female reproductive system [1]. Cisplatin-based sequential chemo-radiation therapy is the standard approach for patients. Verteporfin Inhibits Cervical Carcinoma in FIGO stage IIB to IVA [4]. Various studies have indicated that the development of resistance to cisplatin substantially compromised the efficacy of cisplatin to treat advanced or recurrent cervical cancer [5]. Cisplatin induces severe reproductive toxicity and genotoxicity in mammals [6]. The existing chemotherapy strategy is quite inappropriate for cervical cancer patients with imperative procreation desire. It is necessary to find a new type of chemotherapy agent with less reproductive toxicity on cervical cancer
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