sildenafil-citrate and Lung-Neoplasms

There is now a considerable body of evidence for sildenafil possessing anticancer properties. In this article, we argue the case for testing sildenafil as a lung cancer therapy chemoadjuvant. Currently, lung cancer is a disease with insufficient treatment options, with only 20% of patients responding to systemic chemotherapy, and even incremental potential improvements should be explored. We review the literature concerning the biochemical, physiological and metabolic effects on cancer cells by sildenafil alone, and when combined with chemotherapeutic agents. Most studies have shown that sildenafil is cytotoxic to cancer cells, both as a monotherapy and as a chemoadjuvant. Sildenafil enhances cancer cell apoptosis when used as a chemoadjuvant both in vitro and in vivo. In particular, in rodent experiments sildenafil has decreased tumour size compared to chemotherapy alone. Sildenafil has also been proven as an agent to decrease drug-efflux by cancer cells and increases blood perfusion to lung tissue, which can potentially increase the dosage of chemotherapeutic agents delivered to lung cancer cells compared to healthy tissue. In addition, the proven clinical effects of sildenafil on other lung diseases suggest that it could improve other patient outcomes, such as right ventricular function and quality of life. Sildenafil may also extend the half-life of docetaxel and some small molecule inhibitors used in lung cancer treatment by acting as an inhibitor of CYP3A4. We conclude that the evidence strongly warrants clinical investigation into the use of sildenafil as an agent for the treatment of lung-cancer.

Topics: Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Cell Proliferation; Cytochrome P-450 CYP3A; Drug Repositioning; Humans; Lung Neoplasms; Phosphodiesterase 5 Inhibitors; Sildenafil Citrate

A 24-year-old woman, a baby-sitter with no known comorbidities, presented to the outpatient department with complaints of modified Medical Research Council grade IV breathlessness for 3 months, chest pain, and dry cough for 2 weeks. There was no known disease history, including respiratory, flu-like illness, or connective tissue disorder. There was no use of chemotherapeutic, oral contraceptive drugs, exposure to toxic substances, or smoking. A review of systems was negative for fever, arthralgia, myalgia, Raynaud phenomenon, skin thickening, rash, or leg swelling. The patient had no family history suggestive of a genetic syndrome.

Topics: Chest Pain; Computed Tomography Angiography; Cough; Diagnosis, Differential; Dyspnea; Echocardiography; Endothelin A Receptor Antagonists; Female; Hemangioma, Capillary; Humans; Hypertension, Pulmonary; Lung Neoplasms; Lung Transplantation; Mutation; Oxygen Inhalation Therapy; Phosphodiesterase 5 Inhibitors; Protein Serine-Threonine Kinases; Pulmonary Veno-Occlusive Disease; Pyrimidines; Respiratory Function Tests; Sildenafil Citrate; Sulfonamides; Young Adult

Lung cancer is one of the most frequent types of cancers that lead to death. Sildenafil is a potent inhibitor of phosphodiesterase-5 and showed potential anticancer effects, which has not yet been fully evaluated. Thus, this study aims to investigate the potential anticancer effect of sildenafil in urethane-induced lung cancer in BALB/c mice.. Five-week-old male BALB/c mice were treated with either (i) normal saline only, (ii) sildenafil only 50 mg kg-1/ P.O every other day for the last four successive weeks, (iii) urethane 1.5 gm kg-1 i.p (at day 1 and day 60), (iv) carboplatin after urethane induction, or (v) sildenafil after urethane induction.. It was shown that sildenafil significantly increased the levels of cGMP and Caspase-3 with a reduction of NF-κB, Bcl-2, Cyclin D1, intercellular adhesion molecule 1, matrix metalloproteinase-2 levels and normalisation of Nrf2 along with pronounced improvement in the histological patterns.. These results indicated that sildenafil markedly induces cell cycle arrest, apoptosis and inhibits the metastatic activity through activation of cyclic guanosine monophosphate/protein kinase G pathway and down-regulation of cyclin D1 and nuclear factor kappa light chain enhancer of activated B cells with downstream anti-apoptotic gene Bcl-2, which underscores the critical importance of future using sildenafil in the treatment of lung cancer.

Topics: Animals; Antineoplastic Agents; Apoptosis; Cell Cycle Checkpoints; Cyclic GMP; Cyclic GMP-Dependent Protein Kinases; Cyclin D1; Drug Repositioning; Lung Neoplasms; Matrix Metalloproteinase 2; Mice; Mice, Inbred BALB C; NF-kappa B p50 Subunit; Phosphodiesterase 5 Inhibitors; Proto-Oncogene Proteins c-bcl-2; Sildenafil Citrate; Treatment Outcome

Pemetrexed is an approved therapeutic in NSCLC and ovarian cancer. Our studies focused on the ability of [pemetrexed + sildenafil] exposure to alter the immunogenicity of lung and ovarian cancer cells. Treatment of lung and ovarian cancer cells with [pemetrexed + sildenafil] in vitro rapidly reduced the expression of PD-L1, PD-L2 and ornithine decarboxylase (ODC), and increased the expression of class I MHCA. In a cell-specific fashion, some cells also released the immunogenic nuclear protein HMGB1 into the extracellular environment. [Pemetrexed + sildenafil] reduced the expression of multiple histone deacetylases that was blocked by knock down of autophagy regulatory proteins. [Pemetrexed + sildenafil] lethality was enhanced by the histone deacetylase inhibitors AR42 and sodium valproate; AR42 and valproate as single agents also rapidly reduced the expression of PD-L1, PD-L2 and ODC, and increased expression of MHCA and CerS6. Nitric oxide and CerS6 signaling was required for drug-induced death receptor activation and tumor cell killing. In vivo, [pemetrexed + sildenafil] lethality against lung cancer cells was enhanced by sodium valproate. Using syngeneic mouse lung cancer cells [pemetrexed + sildenafil] enhanced the anti-tumor effects of antibodies directed to inhibit PD-1 or CTLA4. [Pemetrexed + sildenafil] interacted with the anti-PD-1 antibody to strongly enhance tumor infiltration by M1 macrophages; activated NK cells and activated T cells. Our data demonstrate that treatment of tumor cells with [pemetrexed + sildenafil] results in tumor cell killing and via autophagy-dependent downregulation of HDACs, it opsonizes the remaining tumor cells to anti-tumor immunotherapy antibodies.

Topics: Animals; Antineoplastic Agents; Autophagy; Biomarkers, Tumor; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Disease Models, Animal; Drug Synergism; Female; Histone Deacetylase Inhibitors; Humans; Immunotherapy; Lung Neoplasms; Mice; Pemetrexed; Signal Transduction; Sildenafil Citrate; Xenograft Model Antitumor Assays

The combination of pemetrexed and sorafenib has significant clinical activity against a wide variety of tumor types in patients and the present studies were performed to determine whether sildenafil enhances the killing potential of [pemetrexed + sorafenib]. In multiple genetically diverse lung cancer cell lines, sildenafil enhanced the lethality of [pemetrexed + sorafenib]. The three-drug combination reduced the activities of AKT, mTOR and STAT transcription factors; increased the activities of eIF2α and ULK-1; lowered the expression of MCL-1, BCL-XL, thioredoxin and SOD2; and increased the expression of Beclin1. Enhanced cell killing by sildenafil was blocked by inhibition of death receptor signaling and autophagosome formation. Enforced activation of STAT3 and AKT or inhibition of JNK significantly reduced cell killing. The enhanced cell killing caused by sildenafil was more reliant on increased PKG signaling than on the generation of nitric oxide. In vivo sildenafil enhanced the anti-tumor properties of [pemetrexed + sorafenib]. Based on our data we argue that additional clinical studies combining pemetrexed, sorafenib and sildenafil are warranted.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Autophagy; Cell Line, Tumor; Drug Synergism; Humans; Lung Neoplasms; Mice; Neoplasms, Experimental; Niacinamide; Pemetrexed; Phenylurea Compounds; Phosphodiesterase 5 Inhibitors; Sildenafil Citrate; Sorafenib; Xenograft Model Antitumor Assays

K-Ras must localize to the plasma membrane and be arrayed in nanoclusters for biological activity. We show here that K-Ras is a substrate for cyclic GMP-dependent protein kinases (PKGs). In intact cells, activated PKG2 selectively colocalizes with K-Ras on the plasma membrane and phosphorylates K-Ras at Ser181 in the C-terminal polybasic domain. K-Ras phosphorylation by PKG2 is triggered by activation of AMP-activated protein kinase (AMPK) and requires endothelial nitric oxide synthase and soluble guanylyl cyclase. Phosphorylated K-Ras reorganizes into distinct nanoclusters that retune the signal output. Phosphorylation acutely enhances K-Ras plasma membrane affinity, but phosphorylated K-Ras is progressively lost from the plasma membrane via endocytic recycling. Concordantly, chronic pharmacological activation of AMPK → PKG2 signaling with mitochondrial inhibitors, nitric oxide, or sildenafil inhibits proliferation of K-Ras-positive non-small cell lung cancer cells. The study shows that K-Ras is a target of a metabolic stress-signaling pathway that can be leveraged to inhibit oncogenic K-Ras function.

Topics: AMP-Activated Protein Kinases; Animals; Carcinoma, Non-Small-Cell Lung; Cell Line; Cell Line, Tumor; Cell Membrane; Cell Proliferation; Cyclic GMP-Dependent Protein Kinase Type II; Dogs; Endocytosis; Gene Expression Regulation, Neoplastic; Humans; Lung Neoplasms; Madin Darby Canine Kidney Cells; Nitric Oxide; Nitric Oxide Synthase Type III; Phosphorylation; ras Proteins; Serine; Signal Transduction; Sildenafil Citrate

A 43-year-old man presented with dyspnea on exertion. Right heart catheterization demonstrated pulmonary arterial hypertension (PAH). He was treated with bosentan, sildenafil and intravenous epoprostenol. Despite the administration of such intensive therapy, the patient's condition deteriorated to a World Health Organization functional class (WHO-FC) of IV. He participated in a clinical trial of imatinib for PAH. After three months of treatment with imatinib, the chest X-ray and echocardiography findings improved, and the WHO-FC class was III. One year after, however, the PAH worsened again, and the patient died 2.6 years after the first diagnosis. At autopsy, patchy capillary proliferation was observed in the lungs. The definitive diagnosis was pulmonary capillary hemangiomatosis.

Topics: Adult; Antihypertensive Agents; Antineoplastic Agents; Autopsy; Benzamides; Bosentan; Cardiac Catheterization; Dyspnea; Echocardiography; Epoprostenol; Fatal Outcome; Hemangioma, Capillary; Humans; Hypertension, Pulmonary; Imatinib Mesylate; Lung; Lung Neoplasms; Male; Piperazines; Purines; Pyrimidines; Radiography, Thoracic; Sildenafil Citrate; Sulfonamides; Treatment Failure

Post-pneumonectomy respiratory failure is a devastating complication of resection for lung cancer. As proven therapy is limited, we successfully employed a novel medication silfenadil that has been effective in the treatment of pulmonary hypertension.

Topics: Carcinoma, Bronchogenic; Female; Humans; Lung Neoplasms; Middle Aged; Nitric Oxide; Nitric Oxide Donors; Piperazines; Pneumonectomy; Purines; Respiratory Distress Syndrome; Respiratory Insufficiency; Sildenafil Citrate; Sulfones; Treatment Outcome

A 70-year-old man with a past history of lung resection for early stage lung cancer was admitted to our hospital because of worsening exertional dyspnea. Right heart catheterization revealed severe pulmonary arterial hypertension (PAH) with pulmonary vascular resistance of 1671.64 dyne.sec.cm(-5). The patient was treated with sildenafil added to an oral prostacyclin analog, beraprost, and long term oxygen therapy. His exertional dyspnea continued to improve until his sudden death following nasal bleeding. Autopsy revealed marked thickening of pulmonary arteriolar walls, but no recurrence of lung cancer, significant pulmonary embolism or pulmonary parenchymal disease. His PAH could not be explained by the mild airway obstruction or sleep apnea syndrome, and unrelated pulmonary vascular disease was suspected.

Topics: Aged; Epoprostenol; Humans; Hypertension, Pulmonary; Lung Neoplasms; Male; Oxygen Inhalation Therapy; Phosphodiesterase Inhibitors; Piperazines; Pneumonectomy; Pulmonary Artery; Purines; Sildenafil Citrate; Sulfones; Vascular Resistance