Sildenafil enhances cisplatin-induced apoptosis in human breast adenocarcinoma cells

Hassanvand, Fariba; Mohammadi, Tannaz; Ayoubzadeh, Negar; Tavakoli, Atieh; Hassanzadeh, Naiemeh; Sanikhani, Nafiseh Sadat; Azimi, Ali Ipakchi; Khodamoradi, Mehdi; Pourghadamyari, Hossein; Zaimy, Mohamad Ali

doi:10.4103/jcrt.jcrt_675_19

Cited by 11 publications

(3 citation statements)

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“…In vitro studies examining the potentiation of the antitumor activity of cisplatin when given in conjugation with sildenafil on MCF-7 human breast cancer cells showed a dose-dependent cytotoxic effect of sildenafil illustrating its potentiation effect on the chemotherapeutic agent [ 44 ]. Similar results were obtained upon cotreatment of MCF-7 and MDA-MB-468 human breast cancer cells with cisplatin and sildenafil, which was accompanied by a significant increase in accumulation of ROS into the extracellular environment in both breast adenocarcinomas cell lines [ 45 ].…”

Section: In Vitro and In Vivo Applications Of Sildenafil In Cancer Treatmentsupporting

confidence: 74%

The Potential Role of Sildenafil in Cancer Management through EPR Augmentation

Haider

Elsherbeny

Pittalà

et al. 2021

JPM

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Enhanced permeation retention (EPR) was a significant milestone discovery by Maeda et al. paving the path for the emerging field of nanomedicine to become a powerful tool in the fight against cancer. Sildenafil is a potent inhibitor of phosphodiesterase 5 (PDE-5) used for the treatment of erectile dysfunction (ED) through the relaxation of smooth muscles and the modulation of vascular endothelial permeability. Overexpression of PDE-5 has been reported in lung, colon, metastatic breast cancers, and bladder squamous carcinoma. Moreover, sildenafil has been reported to increase the sensitivity of tumor cells of different origins to the cytotoxic effect of chemotherapeutic agents with augmented apoptosis mediated through inducing the downregulation of Bcl-xL and FAP-1 expression, enhancing reactive oxygen species (ROS) generation, phosphorylating BAD and Bcl-2, upregulating caspase-3,8,9 activities, and blocking cells at G0/G1 cell cycle phase. Sildenafil has also demonstrated inhibitory effects on the efflux activity of ATP-binding cassette (ABC) transporters such as ABCC4, ABCC5, ABCB1, and ABCG2, ultimately reversing multidrug resistance. Accordingly, there has been a growing interest in using sildenafil as monotherapy or chemoadjuvant in EPR augmentation and management of different types of cancer. In this review, we critically examine the basic molecular mechanism of sildenafil related to cancer biology and discuss the overall potential of sildenafil in enhancing EPR-based anticancer drug delivery, pointing to the outcomes of the most important related preclinical and clinical studies.

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Section: In Vitro and In Vivo Applications Of Sildenafil In Cancer Treatmentsupporting

confidence: 74%

The Potential Role of Sildenafil in Cancer Management through EPR Augmentation

Haider

Elsherbeny

Pittalà

et al. 2021

JPM

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“…In vitro studies examining the potentiation of the antitumor activity of cisplatin when given in conjugation with sildenafil on MCF-7 human breast cancer cells showed a dose-dependent cytotoxic effect of sildenafil illustrating its potentiation effect on the chemotherapeutic agent [44]. Similar results were obtained upon co-treatment of MCF-7 and MDA-MB-468 human breast cancer cells with cisplatin and sildenafil which was accompanied by a significant increase in accumulation of reactive oxygen species (ROS) into the extracellular environment in both breast adenocarcinomas cell lines [45].…”

Section: In Vitro and In Vivo Applications Of Sildenafil In Cancer Treatmentsupporting

confidence: 59%

The Potential Role of Sildenafil in CancerManagement Through EPR Augmentation

Haider¹,

Elsherbeny²,

Pittalà³

et al. 2021

Preprint

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Enhanced permeation retention (EPR) was a significant milestone discovery by Maeda et al. paving the road for the emerging nanomedicine as a powerful tool in the fight against cancer. Sildenafil is a potent inhibitor of phosphodiesterase 5 (PDE-5) used for treatment of erectile dysfunction (ED) through the relaxation of smooth muscles and the modulation of vascular endothelial permeability. Overexpression of PDE-5 was reported in lung, colon, metastatic breast cancers and bladder squamous carcinoma. Accordingly, there has been a growing interest in using sildenafil as monotherapy or chemoadjuvant in EPR augmentation and management of different types of cancer. Sildenafil had been reported to increase the sensitivity of tumor cells of different origins to the cytotoxic effect of chemotherapeutic agents with augmented apoptosis mediated through inducing the expression of Bad and Bax proapoptotic proteins. It was also reported that the use of sildenafil prior to the administration of Doxorubicin (DOX) increased its EPR-related concentration in breast cancer tissues by 2 folds. Further, a substantial reason of anticancer chemotherapeutic failure is due to multidrug resistance (MDR), exacerbated by the overexpression of ATP-binding cassette (ABC) transporters such as ABCB1 and ABCCs. Sildenafil has demonstrated inhibitory effects on the efflux activity of ABCC4, ABCC5, ABCB1, and ABCG2, ultimately reversing MDR caused by these transporters. In this review, we critically examine the overall potential of sildenafil in enhancing EPR-based anticancer drug delivery pointing up the outcome of the most important related preclinical and clinical studies.

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“…Furthermore, the therapeutic repurposing of PDE5 inhibitors as chemoadjuvant agents has been corroborated by the synergistic effect of sildenafil and cisplatin on the ROS-mediated apoptosis of human mammary adenocarcinomas cells, MCF-7 and MDA-MB-468 [ 89 ]. In both cell lines, co-treatment with cisplatin and sildenafil increased the pro-apoptotic BAX and caspase 3 expression while it reduced the expression of the anti-apoptotic BCL2 only in MCF-7 cells.…”

Section: Challenges Of Targeting Cgmp Signaling In Breast Cancermentioning

confidence: 99%

Pros and Cons of Pharmacological Manipulation of cGMP-PDEs in the Prevention and Treatment of Breast Cancer

Iorio

Ronci

Giuliani

et al. 2021

IJMS

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The cyclic nucleotides, cAMP and cGMP, are ubiquitous second messengers responsible for translating extracellular signals to intracellular biological responses in both normal and tumor cells. When these signals are aberrant or missing, cells may undergo neoplastic transformation or become resistant to chemotherapy. cGMP-hydrolyzing phosphodiesterases (PDEs) are attracting tremendous interest as drug targets for many diseases, including cancer, where they regulate cell growth, apoptosis and sensitization to radio- and chemotherapy. In breast cancer, PDE5 inhibition is associated with increased intracellular cGMP levels, which is responsible for the phosphorylation of PKG and other downstream molecules involved in cell proliferation or apoptosis. In this review, we provide an overview of the most relevant studies regarding the controversial role of PDE inhibitors as off-label adjuvants in cancer therapy.

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Sildenafil enhances cisplatin-induced apoptosis in human breast adenocarcinoma cells

Cited by 11 publications

References 0 publications

The Potential Role of Sildenafil in Cancer Management through EPR Augmentation

The Potential Role of Sildenafil in Cancer Management through EPR Augmentation

The Potential Role of Sildenafil in CancerManagement Through EPR Augmentation

Pros and Cons of Pharmacological Manipulation of cGMP-PDEs in the Prevention and Treatment of Breast Cancer

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