Pre-Exposure to Stress-Inducing Agents Increase the Anticancer Efficacy of Focused Ultrasound against Aggressive Prostate Cancer Cells.

Hakm Y. Murad,Charles A. Kelly,Emma P. Bortz,Damir B. Khismatullin,Namrata Khurana,Partha K. Chandra,Debasis Mondal,Shirley N. Hong,Heng Yu

doi:10.3390/antiox11020341

Hakm Y. Murad, Charles A. Kelly + Show 7 more

Open Access

https://doi.org/10.3390/antiox11020341

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Journal: Antioxidants	Publication Date: Feb 9, 2022
Citations: 4	License type: CC BY 4.0

Affiliation: Tulane University, Lincoln Memorial University

Abstract

Despite the initial success in treatment of localized prostate cancer (PCa) using surgery, radiation or hormonal therapy, recurrence of aggressive tumors dictates morbidity and mortality. Focused ultrasound (FUS) is being tested as a targeted, noninvasive approach to eliminate the localized PCa foci, and strategies to enhance the anticancer potential of FUS have a high translational value. Since aggressive cancer cells utilize oxidative stress (Ox-stress) and endoplasmic reticulum stress (ER-stress) pathways for their survival and recurrence, we hypothesized that pre-treatment with drugs that disrupt stress-signaling pathways in tumor cells may increase FUS efficacy. Using four different PCa cell lines, i.e., LNCaP, C4-2B, 22Rv1 and DU145, we tested the in vitro effects of FUS, alone and in combination with two clinically tested drugs that increase Ox-stress (i.e., CDDO-me) or ER-stress (i.e., nelfinavir). As compared to standalone FUS, significant (p < 0.05) suppressions in both survival and recurrence of PCa cells were observed following pre-sensitization with low-dose CDDO-me (100 nM) and/or nelfinavir (2 µM). In drug pre-sensitized cells, significant anticancer effects were evident at a FUS intensity of as low as 0.7 kW/cm2. This combined mechanochemical disruption (MCD) approach decreased cell proliferation, migration and clonogenic ability and increased apoptosis/necrosis and reactive oxygen species (ROS) production. Furthermore, although activated in cells that survived standalone FUS, pre-sensitization with CDDO-me and/or nelfinavir suppressed both total and activated (phosphorylated) NF-κB and Akt protein levels. Thus, a combined MCD therapy may be a safe and effective approach towards the targeted elimination of aggressive PCa cells.

Highlights

Prostate cancer (PCa) is the second leading cause of cancer-associated morbidity and mortality in elderly men in the United States [1]
In order to suppress the risk of tumor progression, these patients often undergo androgen deprivation therapy (ADT) which presents with significant long-term complications [3,4]
Our current observations show that a similar mechanochemical disruption (MCD) to sensitize aggressive PCa cells to Focused ultrasound (FUS) can be achieved by co-exposure to drugs that increase oxidative stress (Ox-stress) and dysregulate redox signaling, i.e., CDDO-me [25,26], and/or drugs that increase endoplasmic reticulum stress (ER-stress) and are known to target autophagy, i.e., nelfinavir [27,28]

Summary

Introduction

Prostate cancer (PCa) is the second leading cause of cancer-associated morbidity and mortality in elderly men in the United States [1]. The majority of these patients are at a higher risk of complications from the currently available treatment approaches such as surgery and radiation therapy [2]. In order to suppress the risk of tumor progression, these patients often undergo androgen deprivation therapy (ADT) which presents with significant long-term complications [3,4]. Antioxidants 2022, 11, 341 the castration-resistant PCa cells (CRPC) acquire an aggressive and metastatic phenotype by activating androgen-independent signaling pathways [5]. PCa progression to metastatic CRPC (mCRPC) results in a mortality of ~40% of patients within 10 years [6,7]

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