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Harmines inhibit cancer cell growth through coordinated activation of apoptosis and inhibition of autophagy.

ABSTRACT: Harmine and its analogs have long been considered as anticancer agents. In vitro analyses suggested that intercalating DNA or inhibiting topoisomerase might contribute to the cytotoxic effect of this class of compound. However, this idea has not been rigorously tested in intact cells. By synthesizing novel derivatives, here we demonstrate that harmines did not activate the DNA damage response, a cellular signaling commonly induced by agents that intercalate DNA or inhibit topoisomerase. These findings suggest that mechanisms other than DNA intercalating or topoisomerase inhibiting contribute to the toxicity of harmines in vivo. Using a novel N2-benzyl and N9-arylated alkyl compound 10f that has good solubility and stability as the model, we show that harmines strongly inhibited the growth of cancer cells originated from breast, lung, bone and pancreas, but not that of normal fibroblasts. We further show that 10f induced apoptosis and inhibited autophagy in a dose and time-dependent manner. An apoptosis inhibitor suppressed 10f-induced cell death. Together, our results reveal previously unidentified insights into the anticancer mechanism of harmines, supporting future development of this compound class in the treatment of human cancers.

SUBMITTER: Geng X

PROVIDER: S-EPMC5857254 | biostudies-literature | 2018 Mar

REPOSITORIES: biostudies-literature

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Harmines inhibit cancer cell growth through coordinated activation of apoptosis and inhibition of autophagy.

Geng Xinran X Ren Yichang Y Wang Fangfang F Tian Danmei D Yao Xinsheng X Zhang Youwei Y Tang Jinshan J

Biochemical and biophysical research communications 20180301 1

Harmine and its analogs have long been considered as anticancer agents. In vitro analyses suggested that intercalating DNA or inhibiting topoisomerase might contribute to the cytotoxic effect of this class of compound. However, this idea has not been rigorously tested in intact cells. By synthesizing novel derivatives, here we demonstrate that harmines did not activate the DNA damage response, a cellular signaling commonly induced by agents that intercalate DNA or inhibit topoisomerase. These fi ...[more]

PMID: 29501493

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Project description:T‑cell acute lymphoblastic leukemia (T‑ALL) is a common pediatric malignancy, characterized by the abnormal presence of immature T‑cell progenitors. Conventional treatments for T‑ALL fail to prevent or cure the disease, with a high‑risk of recurrence after the first remission. Thus, medical options are in demand to develop novel therapies for patients suffering with T‑ALL. Niclosamide, a traditional oral anti‑helminthic drug, has been reported to be a potential anticancer agent that regulates intracellular signaling pathways. Few studies have yet investigated the effects of niclosamide on the development of T‑ALL. Here, the present study aimed to investigate the anti‑leukemia effects of niclosamide on T‑ALL. We first hypothesized that the suppressive effects of niclosamide on the tumor growth of T‑ALL are exerted by regulating autophagy and apoptosis. Following niclosamide treatment, T‑ALL cell viability was evaluated using MTT assay, and apoptosis with Annexin V/propidium iodide staining. In T‑ALL cells treated with niclosamide, changes in apoptosis‑ and autophagy‑related proteins were analyzed by western blotting. In addition, in an in vivo model, T‑ALL xenograft mice were used to study the anti‑leukemia effects of niclosamide. The results showed that niclosamide significantly reduced the viability of Jurkat and CCRF‑CEM T‑ALL cells in both a dose‑ and time‑dependent manner. Niclosamide significantly activated the early and late phases of apoptosis in Jurkat (at 2 µM) and CCRF‑CEM cells (at 1 µM). Furthermore, niclosamide upregulated protein expression of cleaved caspase‑3 and LC3B, while downregulated those of Bcl‑2 and p62, in a dose‑dependent manner in both Jurkat and CCRF‑CEM cells. The in vivo results showed that niclosamide treatment significantly suppressed tumor growth and the disease progression in T‑ALL xenograft mice by activating cleaved caspase‑3 and LC3B. We conclude that niclosamide plays an anti‑leukemia role, and that it represents a novel approach for the treatment of T‑ALL.

Project description:BackgroundNon-small cell lung cancer (NSCLC) is the leading cause of cancer-related death worldwide. Pemetrexed, a multi-target folate antagonist, has demonstrated efficacy in NSCLC histological subtypes characterized by low thymidylate synthase (TS) expression. Among many other potential targets, histone deacetylase inhibitors (HDACi) modulate TS expression, potentially sensitizing to the cytotoxic action of anti-cancer drugs that target the folate pathway, such as pemetrexed. Since high levels of TS have been linked to clinical resistance to pemetrexed in NSCLC, herein we investigated the molecular and functional effects of combined pemetrexed and ITF2357, a pan-HDACi currently in clinical trials as an anti-cancer agent.ResultsIn NSCLC cell lines, HDAC inhibition by ITF2357 induced histone and tubulin acetylation and downregulated TS expression at the mRNA and protein level. In combination experiments in vitro ITF2357 and pemetrexed demonstrated sequence-dependent synergistic growth-inhibitory effects, with the sequence pemetrexed followed by ITF2357 inducing a strikingly synergistic reduction in cell viability and induction of both apoptosis and autophagy in all cell line models tested, encompassing both adenocarcinoma and squamous cell carcinoma. Conversely, simultaneous administration of both drugs achieved frankly antagonistic effects, while the sequence of ITF2357 followed by pemetrexed had additive to slightly synergistic growth-inhibitory effects only in certain cell lines. Similarly, highly synergistic growth inhibition was also observed in patient-derived lung cancer stem cells (LCSC) exposed to pemetrexed followed by ITF2357. In terms of molecular mechanisms of interaction, the synergistic growth-inhibitory effects observed were only partially related to TS modulation by ITF2357, as genetic silencing of TS expression potentiated growth inhibition by either pemetrexed or ITF2357 and, to a lesser extent, by their sequential combination. Genetic and pharmacological approaches provided an interesting link between the autophagic and apoptotic pathways, and showed that sequential pemetrexed/ITF2357 causes a toxic form of autophagy with consequent activation of a caspase-dependent apoptotic program. In vivo experiments in NSCLC xenografts confirmed that sequential pemetrexed/ITF2357 is feasible and results in increased inhibition of tumor growth and increased mice survival.ConclusionsOverall, these data provide a strong rationale for the clinical development of sequential schedules employing pemetrexed followed by HDACi in NSCLC.

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Harmines inhibit cancer cell growth through coordinated activation of apoptosis and inhibition of autophagy.

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Harmines inhibit cancer cell growth through coordinated activation of apoptosis and inhibition of autophagy.

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