Sulfoquinovosylacylpropanediol is a novel potent radiosensitizer in prostate cancer

Sawada, Yugo; Omoto, Kazuya; Kohei, Naoki; Sakaguchi, Kengo; Miura, Masahiko; Tanabe, Kazunari

doi:10.1111/iju.12753

Cited by 11 publications

(10 citation statements)

References 28 publications

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“…We recently reported that the novel XRT radiosensitizer, SQAP, enhanced growth inhibition in a xenotransplantation mouse model of human PCa . Our findings showed great potential for SQAP as a radiosensitizer in PCa through its ability to oxygenate tumor tissues by the induction of VN; additionally, the effect of tumor site oxygenation persisted at even 30 days after XRT + SQAP treatment.…”

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confidence: 56%

Novel approach for bladder cancer treatment using sulfoquinovosylacylpropanediol as a radiosensitizer

et al. 2015

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Several clinical guidelines have recommended optimal treatments for bladder cancer according to the clinical and pathological stage, and histological grade. Whereas transurethral resection is generally selected for patients with low-grade NMIBC, radical cystectomy should be carried out to manage muscle-invasive bladder cancer and high-grade NMIBC, including bacille Calmette-Gu erin-refractory NMIBC, depending on the patient's performance status, age, comorbidity and other factors. Additionally, bladder-preserving strategies, such as XRT and chemotherapy, have been investigated as alternatives to radical cystectomy. However, XRTtreated patients occasionally experience severe adverse events as a result of radiation dose escalation, which might exceed 40 Gy. Accordingly, lower-dose XRT with a radiosensitizer is desirable, as it could prevent adverse events while yielding anticancer effects similar to conventional XRT.We recently reported that the novel XRT radiosensitizer, SQAP, enhanced growth inhibition in a xenotransplantation mouse model of human PCa. 1 Our findings showed great potential for SQAP as a radiosensitizer in PCa through its ability to oxygenate tumor tissues by the induction of VN; additionally, the effect of tumor site oxygenation persisted at even 30 days after XRT + SQAP treatment. However, the radiosensitizing effects of SQAP in VN might have different outcomes according to the innate radiosensitivity of various tumors, and the mechanisms mediating the long-term effects of oxygenation with XRT + SQAP remain unclear. The two aims of the present study were therefore to evaluate: (i) the effect of VN with XRT + SQAP on bladder cancer; and (ii) the mechanisms mediating the long-term effects of oxygenation with XRT + SQAP.The study protocol is described in Figure 1a. This in vivo study was carried out in accordance with our facility's Guidelines for Animal Experimentation (ID: 15-32). We obtained human bladder cancer cell lines, 5637 and UM-UC-3 (urinary bladder, epithelial, grade II carcinoma), as moderately radiosensitive cells, from the American Type Culture Collection (Manassas, VA, USA). 2 Viable urinary bladder cancer cells (2 9 10 6 ) were injected subcutaneously into the right femurs of male BALB/c Slc-nude mice (aged 6-8 weeks). Once tumor volumes grew to 100-300 mm 3 , 16 mice were divided into four groups based on mean tumor volumes (n = 4 each): control, SQAP alone, XRT alone and XRT + SQAP. Tumor volumes were measured regularly with calipers. Mice were killed for sample collection after 1 month. Immunofluorescent tumor staining was carried out to analyze tumor vessel radiosensitivity. To assess phenotypical tumor changes, such as vascular hyperpermeability after therapy, we labeled intravital blood vessels with tomato lectin and tumor vessel endothelial cells with a CD31-specific antibody, using a previously described procedure. 3,4 The Mann-Whitney U-test was used for statistical comparisons of mean tumor volumes. Differences with P-values <0.05 were considered statistically significant...

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Novel approach for bladder cancer treatment using sulfoquinovosylacylpropanediol as a radiosensitizer

et al. 2015

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“…23). Sawada and colleagues (24) demonstrated that the tumor volume in xenograft models of the human prostate cell lines DU145 and PC3 was reduced after a combination of SQAP administration and radiotherapy. PC3 tumors were fully eradicated by radiation alone, and therefore did not benefit from the addition of SQAP, while DU145 tumors showed little if any response to XRT, but substantial response to SQAP.…”

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confidence: 99%

A Multimodal Molecular Imaging Study Evaluates Pharmacological Alteration of the Tumor Microenvironment to Improve Radiation Response

et al. 2018

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Hypoxic zones in solid tumors contribute to radioresistance, and pharmacologic agents that increase tumor oxygenation prior to radiation, including antiangiogenic drugs, can enhance treatment response to radiotherapy. Although such strategies have been applied, imaging assessments of tumor oxygenation to identify an optimum time window for radiotherapy have not been fully explored. In this study, we investigated the effects of a-sulfoquinovosylacyl-1,3-propanediol (SQAP or CG-0321; a synthetic derivative of an antiangiogenic agent) on the tumor microenvironment in terms of oxygen partial pressure (pO 2), oxyhemoglobin saturation (sO 2), blood perfusion, and microvessel density using electron paramagnetic resonance imaging, photoacoustic imaging, dynamic contrast-enhanced MRI with Gd-DTPA injection, and T2 Ã-weighted imaging with ultrasmall superparamagnetic iron oxide (USPIO) contrast. SCCVII and A549 tumors were grown by injecting tumor cells into the hind legs of mice. Five days of daily radiation (2 Gy) combined with intravenous injection of SQAP (2 mg/kg) 30 minutes prior to irradiation significantly delayed growth of tumor xenografts. Three days of daily treatment improved tumor oxygenation and decreased tumor microvascular density on T2 Ã-weighted images with USPIO, suggesting vascular normalization. Acute effects of SQAP on tumor oxygenation were examined by pO 2 , sO 2 , and Gd-DTPA contrast-enhanced imaging. SQAP treatment improved perfusion and tumor pO 2 (DpO 2 : 3.1 AE 1.0 mmHg) and was accompanied by decreased sO 2 (20%-30% decrease) in SCCVII implants 20-30 minutes after SQAP administration. These results provide evidence that SQAP transiently enhanced tumor oxygenation by facilitating oxygen dissociation from oxyhemoglobin and improving tumor perfusion. Therefore, SQAP-mediated sensitization to radiation in vivo can be attributed to increased tumor oxygenation. Significance: A multimodal molecular imaging study evaluates pharmacological alteration of the tumor microenvironment to improve radiation response. Cancer Res; 78(24); 6828-37. Ó2018 AACR.

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“…1 To understand the interesting findings of this study, knowledge of SQAP is required. SQAP is a sulfoglyco-lipid originally derived from sea urchins expressing α-sulfoquinovosylmonoacylglycerol (SQMG).…”

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“…In the present article, Sawada et al showed that combined treatment with sulfoquinovosylacylpropanediol (SQAP) and X-ray irradiation remodeled the microenvironment in prostate cancer. 1 To understand the interesting findings of this study, knowledge of SQAP is required. SQAP is a sulfoglyco-lipid originally derived from sea urchins expressing α-sulfoquinovosylmonoacylglycerol (SQMG).…”

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Editorial Comment from Dr Miyata and Dr Sakai to Sulfoquinovosylacylpropanediol is a novel potent radiosensitizer in prostate cancer

Miyata

Sakai

2015

Int J of Urology

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Numerous investigators have evaluated the genetic and molecular characteristics of cancer cells. In addition to cancer cells, the tumor microenvironment is of interest, because it plays a crucial role in cell survival and tumor development. In particular, angiogenic and hypoxic environments are recognized major players in aggressive, malignant cancers. Furthermore, changes in the pathological microenvironment induced by treatment can exert anticancer effects. Thus, understanding the microenvironment at the molecular level is essential to develop treatment strategies in patients with malignancies, including prostate cancer.In the present article, Sawada et al. showed that combined treatment with sulfoquinovosylacylpropanediol (SQAP) and X-ray irradiation remodeled the microenvironment in prostate cancer.1 To understand the interesting findings of this study, knowledge of SQAP is required. SQAP is a sulfoglyco-lipid originally derived from sea urchins expressing α-sulfoquinovosylmonoacylglycerol (SQMG). Unfortunately, the anticancer effects of SQAP are not fully understood. Thus, the authors sought to clarify its pathological function. In contrast, a previous report showed that α-SQMG inhibits DNA polymerase activity, thereby inducing apoptosis. Furthermore, α-SQMG can suppress cell viability in the human gastric cancer cell line, NUGC-3.3 Interestingly, α-SQMG was reported to enhance the radiosensitivity of colon cancer cells through regulation of vascular normalization. 4 These findings formed the basis of the present study.One of the most interesting results of the present study is that the tumor volume in xenograft models using DU-145 and PC3 cells was reduced after combination SQAP administration and radiotherapy. Interestingly, the synergistic tumor growth effect of these therapies was detected in DU145 cells, but not PC3 cells. Likewise, the vascular normalization index, calculated by CD34 and α-smooth muscle actin in DU145-derived tumors, was significantly increased by combined therapy, whereas a significant effect was not detected in PC3-derived tumors. The authors speculated that this difference was caused by innate cellular characteristics. We agree with their opinion; however, further studies are necessary to understand the mechanism of SQAP-induced radiosensitization.In recent years, the importance of radiotherapy in prostate cancer monotherapy and combined therapies has increased. 5 Therefore, as the authors have pointed out, more detailed studies are essential for preclinical examination. For example, the anticancer effects of combined SQAP, radiotherapy and hormonal therapy should be evaluated. However, a xenograft model using subcutaneously implanted human cancer cells in athymic nude mice was utilized in the present study. Therefore, readers should be aware that the effects of the immune system and correlation with a prostate-specific environment are lacking in this study. Studies circumventing these limitations will yield important information regarding this treatment strategy.

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Sulfoquinovosylacylpropanediol is a novel potent radiosensitizer in prostate cancer

Cited by 11 publications

References 28 publications

Novel approach for bladder cancer treatment using sulfoquinovosylacylpropanediol as a radiosensitizer

Novel approach for bladder cancer treatment using sulfoquinovosylacylpropanediol as a radiosensitizer

A Multimodal Molecular Imaging Study Evaluates Pharmacological Alteration of the Tumor Microenvironment to Improve Radiation Response

Editorial Comment from Dr Miyata and Dr Sakai to Sulfoquinovosylacylpropanediol is a novel potent radiosensitizer in prostate cancer

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