Anticancer efficacy of a nitric oxide‐modified derivative of bifendate against multidrug‐resistant cancer cells

Abstract

The development of multidrug resistance (MDR) not only actively transports a wide range of cytotoxic drugs across drug transporters but is also a complex interaction between a number of important cellular signalling pathways. Nitric oxide donors appear to be a new class of anticancer therapeutics for satisfying all the above conditions. Previously, we reported furoxan‐based nitric oxide‐releasing compounds that exhibited selective antitumour activity in vitro and in vivo. Herein, we demonstrate that bifendate (DDB)‐nitric oxide, a synthetic furoxan‐based nitric oxide‐releasing derivative of bifendate, effectively inhibits the both sensitive and MDR tumour cell viability at a comparatively low concentration. Interestingly, the potency of DDB‐nitric oxide is the independent of inhibition of the functions and expressions of three major ABC transporters. The mechanism of DDB‐nitric oxide appears to be in two modes of actions by inducing mitochondrial tyrosine nitration and apoptosis, as well as by down‐regulating HIF‐1α expression and protein kinase B (AKT), extracellular signal‐regulated kinases (ERK), nuclear factor κB (NF‐κB) activation in MDR cells. Moreover, the addition of a typical nitric oxide scavenger significantly attenuated all the effects of DDB‐nitric oxide, indicating that the cytotoxicity of DDB‐nitric oxide is as a result of higher levels of nitric oxide release in MDR cancer cells. Given that acquired MDR to nitric oxide donors is reportedly difficult to achieve and genetically unstable, compound like DDB‐nitric oxide may be a new type of therapeutic agent for the treatment of MDR tumours.

Oleanolic Acid Inhibits Epithelial–Mesenchymal Transition of Hepatocellular Carcinoma by Promoting iNOS Dimerization

“…Consistent with above research, we also found high iNOS expression plays a positive role in the prognosis of patients with HCC and suggesting that iNOS can be used as a specific target for HCC treatment. Aberrant protein nitration by nitric oxide, produced by dimerization of iNOS, plays a key role in cancer recurrence and development (48).…”

Combination of betulinic acid with diazen-1-ium-1,2-diolate nitric oxide moiety donating a novel anticancer candidate

“…Low concentration of NO can promote invasion and metastases in different tumor models, and high concentration of NO can inhibit tumor growth and metastases. 32 , 33 NO alone shows a high IC 50 concerning its cytostatic efficacy, while the reported anticancer candidates with NO-releasing residue have much lower IC 50 (from hundreds nanomoles to several micromoles). It has been reported by Heigold et al that NO induced apoptosis selectively in NOX-expressing transformed cells through formation of peroxynitrite in early stages of carcinogenesis.…”

NO-Releasing Enmein-Type Diterpenoid Derivatives with Selective Antiproliferative Activity and Effects on Apoptosis-Related Proteins

“…Generally, high levels of NO (above 400 nM [33]) produced from NO donors can induce apoptosis, inhibit metastasis of tumor cells, and sensitize tumor cells to radiation, immunotherapy, and chemotherapy. Some synthesized NO-releasing compounds have already shown antitumor activity against human carcinoma cells in vitro and in vivo [21][22][23][24][25][26][27][28][29][30][31][32]. Due to the highly reactive nature of NO, it is difficult to predict its biological effects on a given system from single doses even if provided by the longer action of inducible nitric oxide synthase (iNOS).…”

“…Nitric oxide (NO), one of the simplest, odorless, colorless, highly reactive, and biological molecules in nature, is a free radical and a key mediator involved in diverse physiological and pathological processes [16][17][18][19][20]. NO-donating compounds have recently come into focus for the treatment of tumors because NO plays a central role in cell regulatory pathways and is a key signaling molecule involved in the death and apoptosis of tumor cells [21][22][23][24][25][26][27][28][29][30][31][32]. Generally, high levels of NO (above 400 nM [33]) produced from NO donors can induce apoptosis, inhibit metastasis of tumor cells, and sensitize tumor cells to radiation, immunotherapy, and chemotherapy.…”