Doxycycline Induces Apoptosis and Inhibits Proliferation and Invasion of Human Cervical Carcinoma Stem Cells

Yang, Bo; Lu, Yuping; Zhang, Ai; Zhou, Aizhi; Zhang, Lei; Zhang, Lanrong; Gao, Limin; Zang, Yuhua; Tang, Xiuhua; Sun, Lingyun

doi:10.1371/journal.pone.0129138

Cited by 36 publications

(29 citation statements)

References 32 publications

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“…6). Many other antibiotic drugs, such as tigecycline and nitazoxanide, have been recently reported to inhibit various tumour growth in vitro and in vivo (Lamb et al 2015;Senkowski et al 2015;Yang et al 2015), our study further supports the previous work that antibiotic drugs can serve as promising candidates for cancer treatment.…”

Section: Discussionsupporting

confidence: 89%

Doxycycline inhibits proliferation and induces apoptosis of both human papillomavirus positive and negative cervical cancer cell lines

Zhao

Wang

et al. 2016

Can. J. Physiol. Pharmacol.

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The clinical management of cervical cancer remains a challenge and the development of new treatment strategies merits attention. However, the discovery and development of novel compounds can be a long and labourious process. Drug repositioning may circumvent this process and facilitate the rapid translation of hypothesis-driven science into the clinics. In this work, we show that a FDA-approved antibiotic, doxycycline, effectively targets human papillomavirus (HPV) positive and negative cervical cancer cells in vitro and in vivo. Doxycycline significantly inhibits proliferation of a panel of cervical cancer cell lines. It also induces apoptosis of cervical cancer cells in a time- and dose-dependent manner. In addition, the apoptosis induced by doxycycline is through caspase-dependent pathway. Mechanism studies demonstrate that doxycycline affects oxygen consumption rate, glycolysis, and reduces ATP levels in cervical cancer cells. In HeLa xenograft mouse model, doxycycline significantly inhibits growth of tumour. Our in vitro and in vivo data clearly demonstrate the inhibitory effects of doxycycline on the growth and survival of cervical cancer cells. Our work provides the evidence that doxycycline can be repurposed for the treatment of cervical cancer and targeting energy metabolism may represent a potential therapeutic strategy for cervical cancer.

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Section: Discussionsupporting

confidence: 89%

Doxycycline inhibits proliferation and induces apoptosis of both human papillomavirus positive and negative cervical cancer cell lines

Zhao

Wang

et al. 2016

Can. J. Physiol. Pharmacol.

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“…IFN-α exerts its anticancer effects by inhibiting cell proliferation, promoting cell apoptosis, and/or suppressing oncogene expression [4,5,6,7,8,9]. IFN-α has been increasingly used in clinics to treat a wide range of malignancies such as hepatocellular carcinoma (HCC), malignant melanoma, and renal cell cancer (RCC) [10,11,12,13,14].…”

Section: Introductionmentioning

confidence: 99%

Interferon α Induces the Apoptosis of Cervical Cancer HeLa Cells by Activating both the Intrinsic Mitochondrial Pathway and Endoplasmic Reticulum Stress-Induced Pathway

Shi

Cao

Liu

2016

IJMS

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The interferon α (IFN-α) has been often used as a sensitizing agent for the treatment of various malignancies such as hepatocellular carcinoma, malignant melanoma, and renal cell cancer by promoting the apoptosis of thesetumor cell types. However, the effect of IFN-α on cervical cancer remains unknown. In this study, HeLa cells were used as a testing model for the treatment of IFN-α on cervical cancer. The results indicate that IFN-α markedly inhibits the proliferation and induces the apoptosis of HeLa cells. The activation of caspase 3, the up-regulation of both Bim and cleaved poly (ADP-ribose) polymerase (PARP) 1, the down-regulation of Bcl-xL, as well as the release of cytochrome c from mitochondria were significantly induced upon IFN-α treatment, indicating that the intrinsic apoptotic pathway could be activated by IFN-α treatment. In addition, caspase 4—which is involved in the endoplasmic reticulum (ER) stress-induced apoptosis—was activated in response to IFN-α treatment. Knocking down caspase 4 by small interfering RNA (siRNA) markedly reduced the IFN-α-mediated cell apoptosis. However, no significant changes in the expressions of caspases 8 and 10 were observed upon IFN-α treatment, indicating that the apoptosis caused by IFN-α might be independent of the extrinsic apoptotic pathway. These findings suggest that IFN-α may possess anti-cervical cancer capacity by activating cell apoptosis via the intrinsic mitochondrial pathway and caspase-4-related ER stress-induced pathway.

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“…In addition, doxycycline’s in vivo efficacy as single drug and as a combination therapy with temozolomide has been demonstrated in a glioblastoma xenograft mouse model ( Figure 5C ). The inhibitory effects of doxycycline have been demonstrated in cervical cancer and breast cancer [ 7 , 9 , 10 ]. Our data supports the previous work on the anti-cancer activities of doxycycline and adds glioblastoma to the growing list of doxycycline-targeted cancers.…”

Section: Discussionmentioning

confidence: 99%

“…Doxycycline has been shown to suppress the growth of cervical cancer, human breast cancer metastasis, and tumor-sphere formation in a panel of cancer cell lines, including lung cancer and prostate cancer cell lines [ 7 – 9 ]. Besides tumor cells, doxycycline also targets cancer stem cells [ 10 ]. The mechanisms of doxycycline’s anti-cancer activities might be due to its ability in altering energy metabolism [ 8 , 11 ].…”

Section: Introductionmentioning

confidence: 99%

Induction of Mitochondrial Dysfunction and Oxidative Damage by Antibiotic Drug Doxycycline Enhances the Responsiveness of Glioblastoma to Chemotherapy

Tan¹,

Yan²,

Lin³

et al. 2017

Med Sci Monit

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BackgroundInducing mitochondrial dysfunction has been recently demonstrated to be an alternative therapeutic strategy for cancer treatment. Doxycycline is an antibiotic that has been shown to have anti-cancer activities in various cancers by way of targeting mitochondria. In this work, we examined whether doxycycline can be repurposed for glioblastoma treatment.Material/MethodsThe effects of doxycycline on the growth, survival, and mitochondrial metabolisms of glioblastoma were investigated. The efficacy of a combination of doxycycline with temozolomide was examined using xenograft mouse model in total number of 40 mice.ResultsDoxycycline targeted glioblastoma cell lines, regardless of their origin, through inhibiting growth and inducing cell death, accompanied by a significant decrease in proliferating cell nuclear antigen (PCNA) and increase in cleaved caspase-3. In addition, doxycycline significantly sensitized glioblastoma cell response to temozolomide in vitro and in vivo. Mechanistically, doxycycline disrupted mitochondrial functions through decreasing mitochondrial membrane potential and mitochondrial respiration. Inducing mitochondrial dysfunctions by using doxycycline led to energy crisis, oxidative stress, and damage as shown by the decreased levels of ATP and the elevated levels of mitochondrial superoxide, intracellular ROS, 8-OHdG, protein carbonylation, and lipid peroxidation. An antioxidant N-acetyl-L-cysteine (NAC) significantly abolished the anti-proliferative and pro-apoptotic effects of doxycycline, demonstrating that doxycycline acts on glioblastoma via inducing oxidative stress.ConclusionsIn our study, we show that the antibiotic doxycycline is effective in targeting glioblastoma through inducing mitochondrial dysfunctions and oxidative stress. Our work also demonstrated the importance of mitochondrial metabolism in glioblastoma.

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Doxycycline Induces Apoptosis and Inhibits Proliferation and Invasion of Human Cervical Carcinoma Stem Cells

Cited by 36 publications

References 32 publications

Doxycycline inhibits proliferation and induces apoptosis of both human papillomavirus positive and negative cervical cancer cell lines

Doxycycline inhibits proliferation and induces apoptosis of both human papillomavirus positive and negative cervical cancer cell lines

Interferon α Induces the Apoptosis of Cervical Cancer HeLa Cells by Activating both the Intrinsic Mitochondrial Pathway and Endoplasmic Reticulum Stress-Induced Pathway

Induction of Mitochondrial Dysfunction and Oxidative Damage by Antibiotic Drug Doxycycline Enhances the Responsiveness of Glioblastoma to Chemotherapy

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