Ursolic Acid and Its Nanoparticles Are Potentiators of Oncolytic Measles Virotherapy against Breast Cancer Cells

Abstract

Oncolytic viruses (OVs) and phytochemical ursolic acid (UA) are two efficacious therapeutic candidates in development against breast cancer, the deadliest women’s cancer worldwide. However, as single agents, OVs and UA have limited clinical efficacies. As a common strategy of enhancing monotherapeutic anticancer efficacy, we explored the combinatorial chemovirotherapeutic approach of combining oncolytic measles virus (MV), which targets the breast tumor marker Nectin-4, and the anticancer UA against breast adenocarcinoma. Our findings revealed that in vitro co-treatment with UA synergistically potentiated the killing of human breast cancer cells by oncolytic MV, without UA interfering the various steps of the viral infection. Mechanistic studies revealed that the synergistic outcome from the combined treatment was mediated through UA’s potentiation of apoptotic killing by MV. To circumvent UA’s poor solubility and bioavailability and strengthen its clinical applicability, we further developed UA nanoparticles (UA-NP) by nanoemulsification. Compared to the non-formulated UA, UA-NP exhibited improved drug dissolution property and similarly synergized with oncolytic MV in inducing apoptotic breast cancer cell death. This oncolytic potentiation was partly attributed to the enhanced autophagic flux induced by the UA-NP and MV combined treatment. Finally, the synergistic effect from the UA-NP and MV combination was also observed in BT-474 and MDA-MB-468 breast cancer cells. Our study thus highlights the potential value of oncolytic MV and UA-based chemovirotherapy for further development as a treatment strategy against breast cancer, and the feasibility of employing nanoformulation to enhance UA’s applicability.

Formulation for the Targeted Delivery of a Vaccine Strain of Oncolytic Measles Virus (OMV) in Hyaluronic Acid Coated Thiolated Chitosan as a Green Nanoformulation for the Treatment of Prostate Cancer: A Viro-Immunotherapeutic Approach

“…36 The OMV nanoparticles were tested against BT-474 and MDA-MB-468 breast cancer cells and proved a very potential therapeutic candidate in cancer treatment. 37 It was previously published that the charged nanoparticles showed a higher clearance rate from systemic circulation as compared to neutral particles and the high positive zeta potential promotes the scavenging of the nanoparticles by anionic acidic cancer cells. Oncolytic virus nanoparticles, including foot-and-mouth disease virus (FMD), were fabricated using chitosan (CS) into a 281.2 nm size and with a 13 mV positive electrical charge to assess the anti-fungal potential for mucosal vaccines.…”

Ursolic Acid Inhibits Breast Cancer Metastasis by Suppressing Glycolytic Metabolism via Activating SP1/Caveolin-1 Signaling

“…Previous studies also reported that the average content of ursolic acid in the fresh Oldenlandia diffusa was as high as 7.293 ± 2.776 mg/g ( 30 ). More importantly, ursolic acid has been reported to exhibit a wide antitumor spectrum and could inhibit multiple solid tumors including breast cancer ( 31 , 32 ), colorectal cancer ( 33 , 34 ), cervical cancer ( 35 ), pancreatic cancer ( 36 ) and prostate cancer ( 37 ). Several clinical trials have also suggested that ursolic acid supplementation was well-tolerated with manageable toxicity, and could potentially improve patient remission rates in subjects with advanced solid tumors ( 38 , 39 ).…”

“…These results suggest that ursolic acid may be an ideal glycolytic inhibitor with low toxicity and economical characteristic. Noteworthy, it has been reported that ursolic acid is highly hydrophobic which leads to its disappointing systemic bioavailability and relatively short half-life in the circulation ( 31 , 46 ). To improve its clinical applicability, ursolic acid-loaded formulations such as liposomes, nanoliposomes, nanocrystals, solid dispersions and nanoparticles are strongly encouraged.…”

“…To improve its clinical applicability, ursolic acid-loaded formulations such as liposomes, nanoliposomes, nanocrystals, solid dispersions and nanoparticles are strongly encouraged. Notably, ursolic acid-loaded nanoparticles ( 31 ) and liposomes ( 46 ) have been successfully prepared recently, and were found to be very effective in solubilizing and delivering ursolic acid. It has been reported that the peak plasma concentration was 4153.4 ng/ml (approximately 9.1 μM) in humans given a single injection of ursolic acid nanoliposomes at an average dose of 98 mg/m 2 body surface area (an average is 1.7 m 2 for adult males) ( 47 ).…”

Ursolic acid: a natural modulator of signaling networks in different cancers

“…The pharmacological properties of UA will be greatly altered depending upon the type and composition of the carrier nanoparticle including particle size, potential charges and biomimetic properties. In case of breast cancer UA nanoparticle delivery and its anti-cancer properties have been observed with positive results [ 150 ], however each type of cancer has its unique biological properties and various pathways are modulated. In vitro studies of various types of UA nanoparticle drug delivery systems are required to check their therapeutic potential, mechanisms of action, bioavailability, and cytotoxicity.…”