Chemosensitization of Cancer In vitro and In vivo by Nitric Oxide Signaling

Abstract

Purpose: Hypoxia contributes to drug resistance in solid cancers, and studies have revealed that low concentrations of nitric oxide (NO) mimetics attenuate hypoxia-induced drug resistance in tumor cells in vitro. Classic NO signaling involves activation of soluble guanylyl cyclase, generation of cyclic GMP (cGMP), and activation of cGMP-dependent protein kinase. Here, we determined whether chemosensitization by NO mimetics requires cGMP-dependent signaling and whether low concentrations of NO mimetics can chemosensitize tumors in vivo. Experimental Design: Survival of human prostate and breast cancer cells was assessed by clonogenic assays following exposure to chemotherapeutic agents. The effect of NO mimetics on tumor chemosensitivity in vivo was determined using a mouse xenograft model of human prostate cancer. Drug efflux in vitro was assessed by measuring intracellular doxorubicin-associated fluorescence. Results: Low concentrations of the NO mimetics glyceryl trinitrate (GTN) and isosorbide dinitrate attenuated hypoxia-induced resistance to doxorubicin and paclitaxel. Similar to hypoxiainduced drug resistance, inhibition of various components of the NO signaling pathway increased resistance to doxorubicin, whereas activation of the pathway with 8-bromo-cGMP attenuated hypoxia-induced resistance. Drug efflux was unaffected by hypoxia and inhibitors of drug efflux did not significantly attenuate hypoxia-induced chemoresistance. Compared with mice treated with doxorubicin alone, tumor growth was decreased in mice treated with doxorubicin and a transdermal GTN patch. The presence of GTN and GTN metabolites in plasma samples was confirmed by gas chromatography. Conclusion: Tumor hypoxia induces resistance to anticancer drugs by interfering with endogenous NO signaling and reactivation of NO signaling represents a novel approach to enhance chemotherapy.

Hypoxia Increases Tumor Cell Shedding of MHC Class I Chain-Related Molecule: Role of Nitric Oxide

“…Hypoxia contributes to malignant progression in cancer through the stimulation of tumor cell phenotypes that include increased invasive and metastatic potential, as well as resistance to radiation and chemotherapy (5)(6)(7)(8). Because these are survival traits selected by hypoxia, it is also possible that exposure to low levels of oxygen leads to adaptive responses that allow tumor cells to escape from immune surveillance.…”

Nitric oxide (NO) enhances pemetrexed cytotoxicity via NO‑cGMP signaling in lung adenocarcinoma cells in�vitro and in�vivo

“…In a randomized phase 2 trial, a combination of GTN plus vinorelbine and cisplatin was shown to improve the response rate and time to progression in comparison with vinorelbine and cisplatin alone in previously untreated patients with stage IIIB/IV NSCLC (38). Furthermore, the NO-cGMP signaling pathway has been reported to have a strong association with NO-induced attenuation of chemoresistance under hypoxic conditions (30). It is noteworthy that this attenuation was not found under normoxic conditions (31).…”

“…Activated p53 in tumor tissues promotes the apoptosis of cancer cells by p53-dependent anticancer agents, including cisplatin and vinorelbine (16). Furthermore, NO-mimetics have been reported to attenuate hypoxia-induced drug resistance via cyclic guanosine monophosphate (cGMP)-dependent signaling (30). NO donors may be a promising novel therapy in combination with anticancer drugs.…”

Itinéraire d’un agent double

“…De même, combiné à l'oxaliplatine, le NCX-4040 a montré, in vivo, une activité antitumorale contre les tumeurs coliques humaines résistantes ou non à la doxorubicine 3 [36]. Enfin, la trinitrine, ou glycéryl trinitrate (GTN), un autre donneur de NO, sensibilise, in vivo, à la doxorubicine les tumeurs de la prostate humaine [37].…”