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Theaflavin (TF) and epigallocatechin‐3‐gallate (EGCG) both have been reported previously as microtubule depolymerizing agents that also have anticancer effects on various cancer cell lines and in animal models. Here, we have applied TF and EGCG in combination on HeLa cells to investigate if they can potentiate each other to improve their anticancer effect in lower doses and the underlying mechanism. We found that TF and EGCG acted synergistically, in lower doses, to inhibit the growth of HeLa cells. We found the combination of 50 µg/mL TF and 20 µg/mL EGCG to be the most effective combination with a combination index of 0.28. The same combination caused larger accumulation of cells in the G 2/M phase of the cell cycle, potent mitochondrial membrane potential loss, and synergistic augmentation of apoptosis. We have shown that synergistic activity might be due to stronger microtubule depolymerization by simultaneous binding of TF and EGCG at different sites on tubulin: TF binds at vinblastine binding site on tubulin, and EGCG binds near colchicines binding site on tubulin. A detailed mechanistic analysis revealed that stronger microtubule depolymerization caused effective downregulation of PI3K/Akt signaling and potently induced mitochondrial apoptotic signals, which ultimately resulted in the apoptotic death of HeLa cells in a synergistic manner.

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Abstract— Adenosine triphosphatase (ATPase) activities of brain microsomal and synaptosomal preparations are inhibited by imipramine [5‐(3′‐dimethylamino propyl)‐10, 11‐dihy‐dro‐5H‐dibenz (b,f) azepine] in vitro, whereas microsomal ATPase activity is stimulated and synaptosomal ATPase activity remains unaltered under in vivo imipramine treatment. The inhibition of ATPase activity can to some extent be counteracted by spermine [N, N′‐bis(3 aminopropyl)‐1,4‐butanediamine]. Determination of Km values from double reciprocal plots (activity‐1 vs. ATP mM‐1) under drug and spermine‐treated conditions appear to indicate that spermine can to some extent imparta stabilizing effect mainly on the microsomal membrane ATPase, preventing inhibition in presence of imipramine in vitro, although spermine has no effect on the already destabilized membrane ATPase. Spermine exerts a stabilizing effect on membrane ATPase possibly by increasing the affinity of the enzyme for the substrate.

Chronic arsenic (As) poisoning is mostly due to subsoil water contaminated with As and its salts. Exposure to As has been found to cause an elevation in reactive oxygen species (ROS), leading to the damage of DNA and proteins, and it also causes immunotoxicity. Treatment regimens are primarily based on chelation therapy and amino acid and vitamin supplementations. Recent studies have established that natural products display effective and progressive relief from arsenicosis without any side effects. β-glucogallin (BGG), a gallo-tannin natural product, is reported to possess anti-oxidant and anti-inflammatory properties. In the present study, we aim to observe the protective role of BGG against As-induced cytotoxicity, apoptosis, mitochondrial dysfunction, and the underlying mechanisms in RAW 264.7 macrophage cells. We found that BGG alleviates As-induced ROS, apoptosis, and mitochondrial dysfunction in RAW 264.7 macrophage cells. Thus, BGG can be used therapeutically to prevent As-induced toxicity.