Tranilast-induced stress alleviation in solid tumors improves the efficacy of chemo- and nanotherapeutics in a size-independent manner

Abstract

Accumulation of mechanical stresses during cancer progression can induce blood and lymphatic vessel compression, creating hypo-perfusion, hypoxia and interstitial hypertension which decrease the efficacy of chemo- and nanotherapies. Stress alleviation treatment has been recently proposed to reduce mechanical stresses in order to decompress tumor vessels and improve perfusion and chemotherapy. However, it remains unclear if it improves the efficacy of nanomedicines, which present numerous advantages over traditional chemotherapeutic drugs. Furthermore, we need to identify safe and well-tolerated pharmaceutical agents that reduce stress levels and may be added to cancer patients’ treatment regimen. Here, we show mathematically and with a series of in vivo experiments that stress alleviation improves the delivery of drugs in a size-independent manner. Importantly, we propose the repurposing of tranilast, a clinically approved anti-fibrotic drug as stress-alleviating agent. Using two orthotopic mammary tumor models, we demonstrate that tranilast reduces mechanical stresses, decreases interstitial fluid pressure (IFP), improves tumor perfusion and significantly enhances the efficacy of different-sized drugs, doxorubicin, Abraxane and Doxil, by suppressing TGFβ signaling and expression of extracellular matrix components. Our findings strongly suggest that repurposing tranilast could be directly used as a promising strategy to enhance, not only chemotherapy, but also the efficacy of cancer nanomedicine.

Sequential Targeting TGF‐β Signaling and KRAS Mutation Increases Therapeutic Efficacy in Pancreatic Cancer

“…In details, we investigated the expression level of pSmad2/3 after incubating TGF‐β‐activated NIH3T3 cells with fraxinellone free drug (Frax) and Frax‐NP‐CGKRK. The antiasthmatic drug tranilast, which possessed antifibrotic effect on tumor‐bearing mice, served as the positive control. Clearly, Frax and Frax‐NP‐CGKRK treatments reversed the increments of pSmad2/3 expression that promoted by TGF‐β (Figure B,C).…”

In uteroestrogenic endocrine disruption alters the stroma to increase extracellular matrix density and mammary gland stiffness

“…The elastic modulus of mammary glands was determined using an unconfined compression protocol, as previously described Papageorgis et al 2017;Polydorou et al 2017). Following in utero exposures, the fourth inguinal mammary glands were harvested from mice at either 4 weeks or 12 weeks of age, for each treatment group.…”

On the impact of chemo-mechanically induced phenotypic transitions in gliomas

“…This can be understood as a stress-alleviation treatment, in which the tumor is treated with matrix degrading agents to decrease tissue stiffness. In fact, a decrease in stiffness, and thus in mechanical stress levels, may lead to less malignant tumor phenotypes in terms of a reduction in IW 34 . This is shown in Figure 5C, in which the difference between IW at α = 5 × 10 2 Pa and α = 5 × 10 3 Pa is displayed over the (D, r) space.…”

“…33 with mechanical-driven phenotypic transitions, and (ii) to evaluate the effects of a stress-alleviation treatment on glioma progression and invasion. Models describing the application of stress-alleviation treatments already exist in the literature 34 ; however, to the authors knowledge, the influence of cellular phenotypic transitions -resulting from these microenvironmental treatments -on tumor progression have not been investigated yet.…”