RDH1 is one of several enzymes that catalyze the first of two reactions to convert retinol into alltrans-retinoic acid (atRA). Here we show that Rdh1-null mice fed a low-fat diet gain more weight as adiposity (17% males, 13% females) than wild-type mice by 20 weeks old, despite not consuming more calories nor decreasing activity. Glucose intolerance and insulin resistance develops following increased adiposity. Despite the increase in white fat pads, epididymal white adipose does not express Rdh1, nor does muscle. Brown adipose tissue (BAT) and liver express 3

While patient-specific targeting of cellular growth and viability pathways dominates current approaches in anti-cancer therapeutics development, appreciation for the strategy of targeting transformation-dependent alterations in cellular organelle structure and function continues to grow. Here we discuss the lysosome as an anti-cancer target, highlighting its role as a key mediator of cell death. As the major degradative compartment of the cell, the lysosome houses dozens of destructive enzymes and is responsible for the breakdown of both internal and external molecules Note to the Reader: This chapter is part of the book Breast Cancer (ISBN: 978-0-6453320-3-2), scheduled for publication in July 2022. The book is being published by Exon Publications,

The resistance of cancer cell subpopulations, including cancer stem cell (CSC) populations, to apoptosis-inducing chemotherapeutic agents is a key barrier to improved outcomes for cancer patients. The cationic amphiphilic drug hexamethylene amiloride (HMA) has been previously demonstrated to efficiently kill bulk breast cancer cells independent of tumor subtype or species but acts poorly toward non-transformed cells derived from multiple tissues. Here, we demonstrate that HMA is similarly cytotoxic toward breast CSC-related subpopulations that are resistant to conventional chemotherapeutic agents, but poorly cytotoxic toward normal mammary stem cells. HMA inhibits the sphere-forming capacity of FACS-sorted human and mouse mammary CSC-related cells in vitro, specifically kills tumor but not normal mammary organoids ex vivo, and inhibits metastatic outgrowth in vivo, consistent with CSC suppression. Moreover, HMA inhibits viability and sphere formation by lung, colon, pancreatic, brain, liver, prostate, and bladder tumor cell lines, suggesting that its effects may be applicable to multiple malignancies. Our observations expose a key vulnerability intrinsic to cancer stem cells and point to novel strategies for the exploitation of cationic amphiphilic drugs in cancer treatment.

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