A water-soluble formulation of CoQ10 (WS-CoQ10) was shown to stabilize mitochondria and prevent oxidative stress-induced neuronal death. Presenilin-1 (PS-1)-mutated Alzheimer's Disease (AD) fibroblasts (PSAF) were used for studying the effects of PS-1 mutation. PS-1 mutation correlated to increased reactive oxygen species (ROS) production and stress induced premature senescence (SIPS) in PSAF; WS-CoQ10 treatment decreased ROS generation, increased population doublings, and postponed SIPS. Treated PSAF had higher PCNA expression, and lower levels of MnSOD, p21, p16Ink4A, and Rb. WS-CoQ10 caused the resumption of autophagy in PSAF. Thus, WS-CoQ10 as inhibitor of SIPS and ameliorator of autophagy could be an effective prophylactic/therapeutic agent for AD.

The natural compound pancratistatin (PST) is a non-genotoxic inducer of apoptosis in a variety of cancers. It exhibits cancer selectivity as non-cancerous cells are markedly less sensitive to PST. Nonetheless, PST is not readily synthesized and is present in very low quantities in its natural source to be applied clinically. We have previously synthesized and evaluated several synthetic analogues of 7-deoxypancratistatin, and found that JC-TH-acetate-4 (JCTH-4), a C-1 acetoxymethyl analogue, possessed similar apoptosis inducing activity compared to PST. In this study, notoriously chemoresistant osteosarcoma (OS) cells (Saos-2, U-2 OS) were substantially susceptible to JCTH-4-induced apoptosis through mitochondrial targeting; JCTH-4 induced collapse of mitochondrial membrane potential (MMP), increased reactive oxygen species (ROS) production in isolated mitochondria, and caused release of apoptosis inducing factor (AIF) and endonuclease G (EndoG) from isolated mitochondria. Furthermore, JCTH-4 selectively induced autophagy in OS cells. Additionally, we investigated the combinatory effect of JCTH-4 with the natural compound curcumin (CC), a compound found in turmeric spice, previously shown to possess antiproliferative properties. CC alone had no observable effect on Saos-2 and U-2 OS cells. However, when present with JCTH-4, CC was able to enhance the cytotoxicity of JCTH-4 selectively in OS cells. Such cytotoxicity by JCTH-4 alone and in combination with CC was not observed in normal human osteoblasts (HOb) and normal human fetal fibroblasts (NFF). Therefore, this report illustrates a new window in combination therapy, utilizing a novel synthetic analogue of PST with the natural compound CC, for the treatment of OS.

The natural compound pancratistatin (PST), isolated from the Hymenocallis littoralis plant, specifically induces apoptosis in many cancer cell lines. Unlike many other chemotherapeutics, PST is not genotoxic and has minimal adverse effects on non-cancerous cells. However, its availability for preclinical and clinical work is limited due to its low availability in its natural source and difficulties in its chemical synthesis. Several synthetic analogues of 7-deoxypancratistatin with different modifications at C-1 were synthesized and screened for apoptosis inducing activity in human colorectal cancer (CRC) cells. We found that a C-1 acetoxymethyl derivative of 7-deoxypancratistatin, JC-TH-acetate-4 (JCTH-4), was effective in inducing apoptosis in both p53 positive (HCT 116) and p53 negative (HT-29) human CRC cell lines, demonstrating similar efficacy to that of natural PST. JCTH-4 was able to decrease mitochondrial membrane potential (MMP), increase levels of reactive oxygen species in isolated mitochondria, cause release of the apoptogenic factor cytochrome c (Cyto c) from isolated mitochondria, and induce autophagy in HCT 116 and HT-29 cells. Interestingly, when JCTH-4 was administered with tamoxifen (TAM), there was an enhanced effect in apoptosis induction, reactive oxygen species (ROS) production and Cyto c release by isolated mitochondria, and autophagic induction by CRC cells. Minimal toxicity was exhibited by a normal human fetal fibroblast (NFF) and a normal colon fibroblast (CCD-18Co) cell line. Hence, JCTH-4 is a novel compound capable of selectively inducing apoptosis and autophagy in CRC cells alone and in combination with TAM and may serve as a safer and more effective alternative to current cancer therapies.

Pancreatic cancer is amongst the deadliest cancers in the world. It is associated with poor prognosis, is notorious for developing chemoresistance, and very few approved chemotherapeutics are available to treat this disease. The natural compound pancratistatin (PST) has shown to effectively induce cytotoxicity selectively in numerous cancer cell types. However, it is present in only minute quantities in its natural source and many complications have burdened its chemical synthesis. We have overcome these bottlenecks by synthesizing a C-1 acetoxymethyl analogue of 7-deoxypancratistatin, JC-TH-acetate-4 (JCTH-4), which we have shown to have similar selective anti-cancer activity to that of PST. In this report, we show JCTH-4 to be a potent chemotherapeutic against pancreatic cancer cells (BxPC-3, PANC-1). It induced apoptosis selectively in BxPC-3 and PANC-1 cells by targeting the mitochondria; it dissipated mitochondrial membrane potential, caused release of apoptogenic factors, and in isolated mitochondria, increased the generation of reactive oxygen species. Furthermore, JCTH-4 selectively induced autophagy in pancreatic cancer cells while normal human fetal fibroblasts were markedly less sensitive to JCTH-4 insult. Altogether, this study outlines JCTH-4 as a potentially safe and effective chemotherapeutic agent in treating notoriously chemoresistant pancreatic cancer.

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