Selective Targeting of Cancer Cells by Oxidative Vulnerabilities with Novel Curcumin Analogs

Abstract

Recently, research has focused on targeting the oxidative and metabolic vulnerabilities in cancer cells. Natural compounds like curcumin that target such susceptibilities have failed further clinical advancements due to the poor stability and bioavailability as well as the need of high effective doses. We have synthesized and evaluated the anti-cancer activity of several monocarbonyl analogs of curcumin. Interestingly, two novel analogs (Compound A and I) in comparison to curcumin, have increased chemical stability and have greater anti-cancer activity in a variety of human cancer cells, including triple-negative, inflammatory breast cancer cells. In particular, the generation of reactive oxygen species was selective to cancer cells and occurred upstream of mitochondrial collapse and execution of apoptosis. Furthermore, Compound A in combination with another cancer-selective/pro-oxidant, piperlongumine, caused an enhanced anti-cancer effect. Most importantly, Compound A was well tolerated by mice and was effective in inhibiting the growth of human triple-negative breast cancer and leukemia xenografts in vivo when administered intraperitoneally. Thus, exploiting oxidative vulnerabilities in cancer cells could be a selective and efficacious means to eradicate malignant cells as demonstrated by the curcumin analogs presented in this report with high therapeutic potential.

The independence of and associations among apoptosis, autophagy, and necrosis

“…Moreover, although cancer cells have developed redox adaptation mechanisms to survive in a high oxidative environment, extensive studies have suggested that they are more vulnerable to oxidative stress caused by ROS-generating agents than normal cells, providing the selectivity of ROS-based therapies 197 . Exogenous ROS-generating agents used as a single agent or in combination with other standard therapies have shown promise in pre-clinical studies 198 – 200 .…”

Pancreatic Cancer (PDAC): Introduction of Evidence-Based Complementary Measures into Integrative Clinical Management

“…Additionally, by inhibiting NF-κB signaling, curcumin was able to increase cellular uptake of gemcitabine and decrease desmoplasia, and thus decrease chemoresistance [ 238 ]. Preclinical trials have shown that curcumin can work both alone and in combination with chemotherapy to generate anti-PDAC effects [ 80 , 239 ]. In an early xenograft study, curcumin potentiated the effectiveness of gemcitabine in suppressing PDAC tumor formation significantly by ca.…”

In-Vitro and In-Silico Evaluations of Heterocyclic-Containing Diarylpentanoids as Bcl-2 Inhibitors Against LoVo Colorectal Cancer Cells

“…Several downstream mechanistic studies revealed that the remarkable anti-cancer properties of these diarylpentanoids are due to their anti-angiogenic and apoptosis-inducing activities, which resulted from VEGF inhibition and caspases activation, respectively [ 26 , 27 , 28 ]. In addition, cyclic monocarbonyl diarylpentanoids were also found to be effective in-vivo based on their positive suppression against tumor growth in several mice xenograft models [ 29 , 30 ]. Interestingly, recent studies demonstrated that this diarylpentanoid family possesses a curcumin-like safety profile as they were shown to be non-toxic in acute toxicity evaluations of several anti-inflammatory animal models [ 31 , 32 ].…”