Abstract
Histone deacetylase inhibitors (HDACi) are promising therapeutic agents which are currently used in combination with chemotherapeutic agents in clinical trials for cancer treatment including non-small cell lung cancer (NSCLC). However, the mechanisms underlying their anti-tumor activities remain elusive. Previous studies showed that inhibition of HDAC6 induces DNA damage and sensitizes transformed cells to anti-tumor agents such as etoposide and doxorubicin. Here, we showed that depletion of HDAC6 in two NSCLC cell lines, H292 and A549, sensitized cells to cisplatin, one of the first-line chemotherapeutic agents used to treat NSCLC. We suggested that depletion of HDAC6 increased cisplatin-induced cytotoxicity was due to the enhancement of apoptosis via activating ATR/Chk1 pathway. Furthermore, we showed that HDAC6 protein levels were positively correlated with cisplatin IC50 in 15 NSCLC cell lines. Lastly, depletion of HDAC6 in H292 xenografts rendered decreased tumor weight and volume and exhibited increased basal apoptosis compared with the controls in a xenograft mouse model. In summary, our findings suggest that HDAC6 is positively associated with cisplatin resistance in NSCLC and reveal HDAC6 as a potential novel therapeutic target for platinum refractory NSCLC.
Highlights
Lung cancer remains the leading cause of cancer death for both men and women in the United States, claiming more lives annually than the three causes of cancer death combined [1]
Our results indicated that HDAC6 confers cisplatin resistance
We report that HDAC6 plays an important role in cisplatin resistance in non-small cell lung cancer (NSCLC) cell lines
Summary
Lung cancer remains the leading cause of cancer death for both men and women in the United States, claiming more lives annually than the three causes of cancer death (cancers of the breast, colon and prostate) combined [1]. Survival rates for patients with NSCLC remain extremely low, with only 16% of patients alive 5 years after a lung cancer diagnosis. This poor prognosis is explained in part by the large numbers of patients who present with advanced disease, even patients identified at an early-stage experience high rates of relapse in spite of adequate surgical resection [2]. Given that a relatively small population appears to benefit from chemotherapy, many patients are subjected to toxic treatment without clinical benefit. A better understanding of the mechanisms of resistance to platinum-based chemotherapy is required and strategies are needed to identify patients unlikely to benefit from treatment. Novel methods of overcoming platinum resistance may be targeted to these populations
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