Lysosomes as Oxidative Targets for Cancer Therapy

Abstract

Lysosomes are membrane-bound vesicles that contain hydrolases for the degradation and recycling of essential nutrients to maintain homeostasis within cells. Cancer cells have increased lysosomal function to proliferate, metabolize, and adapt to stressful environments. This has made cancer cells susceptible to lysosomal membrane permeabilization (LMP). There are many factors that mediate LMP such as Bcl-2 family member, p53; sphingosine; and oxidative stress which are often altered in cancer. Upon lysosomal disruption, reactive oxygen species (ROS) levels increase leading to lipid peroxidation, mitochondrial dysfunction, autophagy, and reactive iron. Cathepsins are also released causing degradation of macromolecules and cellular structures. This ultimately kills the cancer cell through different types of cell death (apoptosis, autosis, or ferroptosis). In this review, we will explore the contributions lysosomes play in inducing cell death, how this is regulated by ROS in cancer, and how lysosomotropic agents might be utilized to treat cancers.

Genomic landscape and mutational impacts of recurrently mutated genes in cancers

“…Mutations in PTPRD abrogated its function to regulate STAT3 and promoted cancer progression (Funato, Yamazumi, Oda, & Akiyama, 2011;Zhao et al, 2010). In addition, the alterations in cathepsins may disrupt lysosomal trafficking and autophagy, thus led to tumor invasion (Dielschneider, Henson, & Gibson, 2017;White, Mehnert, & Chan, 2015). Recurrent mutations in hydrolases may cause uncontrolled proliferation, differentiation and metastasis, so target tumor cell hydrolases is a good way to treat cancer.…”

Lysosomal storage disorders – challenges, concepts and avenues for therapy: beyond rare diseases

“…The autophagy-lysosome machinery is essential for cancer cell proliferation, metabolism and adaptation to environment stress. In many types of cancer, lysosome biogenesis is increased, which allows the cancer cells to maintain homeostasis during proliferation and to survive under stress conditions (Dielschneider et al, 2017;Kroemer and Jäättelä, 2005). Additionally, lysosomes play an important role in the resistance to chemotherapeutic drugs by either sequestering these compounds or facilitating their exocytosis (Dielschneider et al, 2017;Kroemer and Jäättelä, 2005) (Fig.…”

Highly Potent Rhenium(I) Tricarbonyl Complexes with Dual Anticancer and Anti-Angiogenic Activity Against Colorectal Carcinoma

“…105,106 It is noteworthy to point out that the lysosomes are emerging as very attractive targets in anticancer therapy, and drugs affecting the integrity of lysosomes have been proven to be effective in cancer treatment. [107][108][109][110][111] Due to the fact that the fluorescence of 1 and 4 is visible throughout the entire cytosplasm of HCT-116 cells, it is possible that some cytosolic proteins could be targets of the tested molecules, as recently demonstrated for a Re(I) tricarbonyl isonitrile complex which exerted anticancer activity via the endoplasmic reticulum stress and the accumulation of misfolded proteins. 104 Accordingly, we probed the reactivity of complexes 1 and 4 with hen egg white lysozyme (HEWL), a model protein often employed to investigate metal-protein adducts.…”